Calcium supplement having enhanced absorption

ABSTRACT

Dietary calcium supplements comprising highly bioavailable forms of calcium carbonate and methods of using these calcium carbonate forms to improve calcium balance, strengthen bones, and prevent, treat, and/or ameliorate bone loss associated with osteoporosis are provided.

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application Ser. No. 60/892,183, filed Feb. 28, 2007,and U.S. Provisional Patent Application Ser. No. 60/825,853, filed Sep.15, 2006, the disclosures of which are hereby incorporated by referenceherein.

FIELD OF INVENTION

The present invention relates generally to compositions and methods fordietary calcium supplementation. More particularly, the presentinvention relates to forms of calcium carbonate which provide enhancedabsorption.

BACKGROUND OF THE INVENTION

Calcium is an essential nutrient and the most abundant mineral in thehuman body. Calcium plays a vital role in building healthy teeth andbones, blood clotting, muscle contraction, and nerve function. Mostnotably, calcium reduces the risk of bone loss caused by osteoporosis inboth men and women. Despite these advantages, it has been estimated thathalf of all Americans do not consume sufficient amounts of calcium. Moretroubling, 80% of women, the group at highest risk for developingosteoporosis, do not consume enough calcium.

This deficiency is due in part to the large daily intake of calcium thatis suggested by physicians. The National Academy of Sciences, Instituteof Medicine recommends daily intakes (RDI) of 1,200 mg of elementalcalcium per day for people over 50 years of age and 1,300 mg a day forpeople under 19 years of age. For individuals between these age groups,the recommendation is 1,000 mg per day. Not surprisingly, physiciansrecommend calcium supplements more than any other dietary supplement.

Commercially available calcium supplements employ a wide variety ofcalcium salts, including, for example, calcium carbonate, calciumcitrate, calcium glycerophosphate, calcium oxide, calcium phosphate,calcium pyrophosphate, calcium chloride, calcium lactate, and calciumsulfate. Despite the very different solubilities of these salts, theirabsorption in the intestine is comparable. For example, while calciumcarbonate is insoluble in water and calcium citrate is soluble, isotopictracer methods have established that their bioavailability is similar.In view of the similar bioavailability of various calcium salts, calciumcarbonate has become the most common salt for supplementation because itis comparably inexpensive and delivers more elemental calcium on aweight basis (˜40%) than most other calcium salts. However, theabsorption of calcium carbonate through the intestine, like all calciumsalts, is relatively inefficient. For example, it has been reported thatcalcium carbonate absorption efficiency is about 34.2%±10.1% in adultmen and postmenopausal women. See Heaney, R. P. et al., “Absorption ofcalcium as the carbonate and citrate salts, with some observations onmethod.” Osteoporos. Int 9:19-23 (1999).

Vitamin D is known to be a beneficial adjunct to calcium supplementationbecause it both increases absorption efficiency up to a serum 25-OHvitamin D level of 80 nmol/ml and regulates parathyroid hormone levelswhich in turn regulate bone absorption/resorption of calcium. The aminoacid L-lysine has also been reported to enhance calcium absorptionefficiency in humans and rats. Sec Civitelli et al. “Dietary L-lysineand calcium metabolism in humans,” Nutrition 8: 400-5 (1992); Wassermanet al. “Interrelated effects of L-lysine and other dietary factors onthe gastrointestinal absorption of Calcium 45 in the Rat and Chick.” J.Nutrition 62, 367-376 (1957). However, the efficacy of L-lysinesupplementation has not been established in chronic feeding. Despite thebenefits of calcium supplements, particularly those fortified withVitamin D, it would be desirable to provide a form of calcium for use incalcium supplements and food products having improved absorptioncharacteristics.

It is known in the pharmaceutical industry that an important factorwhich effects the bioavailability of a drug is particle size. There isgenerally an inverse relationship between the particle size ofnonionized particles and absorption through the gut. See Florence etal., “Factors Affecting the Oral Uptake and Translocation of PolystyreneNanoparticles: Histological and Analytical Evidence,” J. Drug Target 3,65-70 (1995). A recent in vitro study showed cellular uptake was greaterfor polystyrene particles in the 100-200 nm size range than for similarsmaller or larger particles. Win et al. “Effects of Particle Size andSurface Coating on Cellular Uptake of Polymeric Nanoparticles for OralDelivery of Anticancer Drugs,” Biomaterials 26, 2713-22 (2005).

However, The effect of particle size on calcium absorption has receivedonly modest attention to date. Rao et al studied the effect of limestonecalcium carbonate particle size on in vivo solubilization and retentionin hens. See K. S. Rao et al., “In Vivo Limstone Solubilization inCommercial Leghorns: Role of Dietary Calcium Level, Limestone ParticleSize, In Vitro Limestone Solubility Rate, and the Calcium Status of theHen,” Poultry Sci., 69:2170-2176 (1990). The authors report that hensconsuming calcium carbonate of particle size between 2 and 5 mm(millimeters) solubilize and retain a greater percentage of calcium thanhens fed calcium carbonate of particle size between 0.5 and 0.8millimeters. The authors state that this is consistent with theirearlier finding that hens fed large particulate limestone retain agreater percentage of calcium than hens fed small particulate limestone,Rao et al, “Influence of Dietary Calcium Level and Particle Size ofCalcium Source on In Vivo Calcium Solubilization by CommercialLeghorns,” Poultry Sci. 68:1499-1505 (1989). It is suggested thatgreater utilization of large particles of calcium carbonate as comparedto small particles results from an increased residence time in thegizzard which provides for gradual metering through the intestine, aspreviously posited by Scott et al, “The Calcium Requirements of LayingHens and Effects of Dietary Oyster Shell Upon Eggshell Quality,” PoultrySci. 50:1055-1063 (1971). In contrast, Guinotte and coworkers reportthat ground calcium carbonate having a particle size less than 0.15 mmimproved calcium retention and tibial ossification in growing chicks ascompared to medium (0.3 to 1.18 mm) and large (1.18 to 4.75 mm) calciumcarbonate particles. See F. Guinotte et al., “The Effects of ParticleSize and Origin of Calcium Carbonate on Performance and OssificationCharacteristics in Broiler Chicks,” Poultry Sci., 70:1908-1920 (1991).Similar studies on particle size and absorption in humans or rodents arelacking.

There is continuing need in the art for calcium forms having high invivo utilization efficiency. It therefore is an object of the presentinvention to identify critical parameters of calcium carbonate powderswhich provide for enhanced bioavailability and to provide such powders.It is another object of the present invention to provide dietarysupplements, foods and the like comprising highly absorbable calciumforms. It is also an object of the invention to provides compositionsand methods for increasing calcium balance. It is further an object ofthe invention to provide composition and methods for preventing,treating, and/or ameliorating the effects of osteoporosis with calciumsupplements, ideally without resort to pharmaceutical intervention.

SUMMARY OF THE INVENTION

In accordance with the foregoing objectives and others, the presentinvention provides calcium carbonate powders, and supplements, foods,and the like comprising such powders, which exhibit unexpectedly highabsorption efficiency, calcium balance, and bone strength.

In one aspect of the invention, a tablet for dietary calciumsupplementation is provided comprising between about 1,600 and about2,500 mg of enhanced absorption calcium carbonate powder. In a variantof this aspect, the tablet comprises between about 1,798 mg and about1,888 mg of enhanced absorption calcium carbonate. The tablet accordingto this aspect of the invention typically has a volume between about0.75 cm³ and about 1.6 cm³, more typically between about 0.90 cm³ andabout 1.1 cm³, and in one embodiment has a volume of about 1 cm³. Thetablet may further comprise at least about 400 I.U. of vitamin D and ispreferably capable of providing at least about 360 mg of absorbableelemental calcium. The enhanced absorption calcium carbonate accordingto this and the following aspects of the invention may have a particlesize distribution characterized, for example, by a D₅₀ value, on avolume basis, between about 9.8 μm and about 13.5 μm, a D₅₀ value, on avolume basis, between about 26.1 μm and about 31.7 μm, and at least 30%of total volume of particles having sizes between about 1 μm and about11 μm.

According to another aspect, a tablet for dietary calciumsupplementation is provided comprising: (i) between about 1,798 andabout 1,888 mg of calcium carbonate powder having the particle sizedistribution of FIG. 12; and (ii) at least about 400 I.U. of vitamin D;and wherein the volume of the tablet is between about 0.90 cm³ and about1.1 cm³.

In another aspect, a tablet for dietary calcium supplementationcomprises between about 800 mg and about 1,400 mg of enhanced absorptioncalcium carbonate powder, and will more typically comprise between about899 mg and about 944 mg of said calcium carbonate. The tablet accordingto this aspect may have a volume between about 0.4 cm³ and about 0.8cm³, or between about 0.4 cm³ and about 0.6 cm³, or may have a volume ofabout 0.5 cm³. The tablet may further comprise at least about 400 I.U.of vitamin D and preferably is capable of providing at least about 180mg of absorbable elemental calcium.

In a related aspect, a tablet for dietary calcium supplementation isprovided comprising: (i) between about 899 mg and about 944 mg ofcalcium carbonate having the particle size distribution of FIG. 12; and(ii) at least about 400 I.U. of vitamin D; wherein the volume of saidtablet is between about 0.4 cm³ and about 0.6 cm³.

In another aspect of the invention, a tablet for dietary calciumsupplementation comprises between about 1,750 and about 3,000 mg ofenhanced absorption calcium carbonate powder and more typically willcomprise between about 1,948 mg and about 2,046 mg of enhancedabsorption calcium carbonate. The tablet may have a volume between about0.8 cm³ and about 1.75 cm³, more typically, between about 1 cm³ andabout 1.2 cm³, or about 1.1 cm³. The tablet may further comprise atleast about 400 I.U. of vitamin D and will preferably provide at leastabout 390 mg of absorbable elemental calcium.

In one aspect related to the preceding aspect, a tablet for dietarycalcium supplementation comprises: (i) between about 1,948 mg and about2,046 mg of calcium carbonate having the particle size distribution ofFIG. 12; and (ii) at least about 400 I.U. of vitamin D; wherein thevolume of the tablet is between about 1 cm³ and about 1.2 cm³.

In a further aspect of the invention, a tablet for dietary calciumsupplementation is provided comprising between about 925 mg and about1,200 mg of enhanced absorption calcium carbonate or between about 974mg and about 1,023 mg of enhanced absorption calcium carbonate. Thetablet may have a volume between about 0.45 cm³ and about 0.8 cm³, andmore typically will have a volume between about 0.5 cm³ and about 0.7cm³, including for example, a volume between about 0.55 cm³ and about0.6 cm³. The tablet may further comprise at least about 400 I.U. ofvitamin D and is preferably capable of providing at least about 195 mgof absorbable elemental calcium.

Another aspect of the invention is a tablet for dietary calciumsupplementation comprising: (i) between about 974 mg and about 1,023 mgof calcium carbonate having the particle size distribution of FIG. 12;and (ii) at least about 400 I.U. of vitamin D; wherein the volume ofsaid tablet is between about 0.5 cm³ and about 0.7 cm³.

In yet another aspect, various methods are provided, including methodsfor providing the daily Adequate Intake (AI) of 1,200 or 1,300 mg ofelemental calcium comprising either (1) administering to an individualin need thereof, a tablet comprising enhanced absorption calciumcarbonate once during the course of a day; or (2) administering to anindividual in need thereof, two tablets comprising enhanced absorptioncalcium carbonate either together or at two times during the course of aday.

In still a further aspect of the invention, a tablet for dietary calciumsupplementation is provided comprising: (i) between about 1,425 andabout 1,575 mg of enhanced absorption calcium carbonate powder; and (2)at least about 500 I.U. of vitamin D, at least about 600 I.U. of vitaminD, at least about 800 I.U. of vitamin D, or at least about 1,000 I.U. ofvitamin D.

In another aspect, a product is provided comprising: (a) a containercomprising a plurality of tablets for dietary calcium supplementation,the tablets comprising between about 1,425 and about 1,575 mg ofenhanced absorption calcium carbonate powder and vitamin D; and (b)instructions on the product labeling, packaging, or insert, for the useof the tablets in a single daily dose to achieve a full day requirementof calcium. This aspect applies equally to any of the tablets describesabove.

Another aspect relates to method a for providing the daily AdequateIntake (AI) of 1,000 mg of elemental calcium comprising administering toan individual in need thereof, once during the course of a day for aperiod of at least about eight weeks, a tablet comprising between about1,425 and about 1,575 mg of enhanced absorption calcium carbonate powderand at least about 400 I.U. of vitamin D.

Yet another aspect relates to a method comprising: (i) providing a brandof calcium supplements in tablet form, said brand of calcium supplementscomprising a first calcium carbonate powder; and (2) reformulating saidbrand of calcium supplements by replacing all or a portion of said firstcalcium carbonate powder in said calcium supplements with enhancedabsorption calcium carbonate powder having an absorption efficiency ofelemental calcium greater than that of said first calcium carbonatepowder.

Functional foods and confectionery products comprising enhancedabsorption calcium carbonate powder and optionally, vitamin D, are alsoprovided.

Pharmaceutical compositions are also provided, which may comprise, forexample: (1) calcium carbonate powder having a particle sizedistribution characterized by a D₅₀ value, on a volume basis, betweenabout 9.8 μm and about 13.5 μm, a D₉₀ value, on a volume basis, betweenabout 26.1 μm and about 31.7 μm, and at least 30% of total volume ofparticles having sizes between about 1 μm and about 11 μm; and (2) atleast about 400 I.U. of vitamin D.; and (3) a bisphosphonate drug.

In an additional aspect of the invention, a multi-vitamin is providedcomprising:

(1) enhanced absorption calcium carbonate powder;

(2) one or more vitamins selected from the group consisting of:

-   -   between 1 and about 35,000 IU of vitamin A;    -   between 1 and about 1,000 mg of vitamin C;    -   between 1 and about 4,000 IU of vitamin D;    -   between 1 and about 450 IU of vitamin E;    -   between 1 and about 250 mcg of vitamin K;    -   between 1 and about 15 mg of vitamin B-1 (thiamin);    -   between 1 and about 17 mg of vitamin B-2 (riboflavin);    -   between 1 and about 200 mg of vitamin B-3 (niacin);    -   between 1 and about 100 mg of vitamin B-5 (pantothenic acid);    -   between 1 and about 30 mg of vitamin B-6 (pyridoxine);    -   between 1 and about 4,000 mcg of vitamin B-9 (folic acid);    -   between 1 and about 250 mcg of vitamin B-12 (cobalamin); and    -   between 1 and about 1,000 meg of vitamin H (biotin);    -   and combinations thereof; and

(3) one or more minerals selected from the group consisting of:

-   -   between 1 and about 180 mg of iron;    -   between 1 and about 1,100 mg of phosphorous;    -   between 1 and about 1,500 mcg of iodine;    -   between 1 and about 4,000 mg of magnesium;    -   between 1 and about 150 mg of zinc;    -   between 1 and about 600 mcg of selenium;    -   between 1 and about 20 mg of copper;    -   between 1 and about 20 mg of manganese;    -   between 1 and about 2,000 mcg of chromium; and between 1 and        about 750 mcg of molybdenum;    -   between 0.001 and about 0.1 mg of tin;    -   between 1 and about 100 mcg of vanadium;    -   between 0.5 and 50 mcg of nickel;    -   and combinations thereof.

These and other aspects of the invention may be more clearly understoodby reference to the following detailed description of the invention andthe appended claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 illustrates the calcium regulatory system in humans.

FIG. 2 shows the particle size distribution of the OMYA-Cal® USP-10-AZcalcium carbonate powder according to the invention (shown as theaverage of three samples, designated X _((A,B,C))), expressed as percentdifferential volume between channel diameters of the Coulter ParticleSize Analyzer, compared to the conventional OMYA-Cal® USP-15-AZ powder(shown as the average of three samples, designated X _((D,E,F))). Asillustrated, the OMYA-Cal® USP-40-AZ calcium carbonate powder providessubstantially more powder volume in the intermediate particle size rangethan does the conventional OMYA-Cal® USP-15-AZ powder.

FIG. 3 shows the effect of the diets listed in Tables 1 and 2,comprising different calcium sources, vitamin D status, and L-lysinestatus, on the absorption efficiency in rats after two days of calciumsupplementation.

FIG. 4 shows the effect of the diets listed in Tables 1 and 2,comprising different calcium sources, vitamin D status, and L-lysinestatus, on the calcium balance in rats after two days of calciumsupplementation.

FIG. 5 shows the effect of the diets listed in Table 1 and 2, comprisingdifferent calcium sources, vitamin D status, and L-lysine status, on theabsorption efficiency in rats after eight weeks of calciumsupplementation.

FIG. 6 shows the effect of the diets listed in Table 1 and 2, comprisingdifferent calcium sources, vitamin D status, and L-lysine status, on thecalcium balance in rats after eight weeks of calcium supplementation.

FIG. 7 compares the calcium retention in rats after two days (weanlings)and after eight weeks (young adults) on Diets 2 and 5 listed in Tables 1and 2.

FIG. 8 shows the effect of the diets listed in Table 1 and 2, comprisingdifferent calcium sources, vitamin D status, and L-lysine status, on thepeak break force of femurs from rats after eight weeks of calciumsupplementation.

FIG. 9 shows the particle size distribution of three samples (A, B, andC) of OMYA-Cal® USP-10-AZ calcium carbonate powder as measured on aCoulter Particle Size Analyzer, expressed as cumulative volume percentbetween each channel diameter, plotted on a logarithmic scale.

FIG. 10 shows the particle size distribution of three samples (A, B, andC) of OMYA-Cal® USP-10-AZ calcium carbonate powder as measured on aCoulter Particle Size Analyzer, expressed as cumulative volume percentof particle size less than the channel diameter, plotted on alogarithmic scale.

FIG. 11 shows the particle size distribution corresponding to the meanat each channel diameter, designated X of three samples (A, B, and C) ofOMYA-Cal® USP-10-AZ calcium carbonate powder as measured on a CoulterParticle Size Analyzer, expressed as cumulative volume percent betweeneach channel diameter, plotted on a logarithmic scale.

FIG. 12 shows the particle size distribution corresponding to the meanat each channel diameter, designated X _((A,B,C)), of three samples (A,B, and C) of OMYA-Cal® USP-10-AZ calcium carbonate powder as measured ona Coulter Particle Size Analyzer, expressed as cumulative volume percentof particles of size less than the channel diameter, plotted on alogarithmic scale.

FIG. 13 shows the particle size distribution corresponding to the meanat each channel diameter, designated X _((A,B,C)), of three samples (A,B, and C) of OMYA-Cal® USP-10-AZ calcium carbonate powder as measured ona Coulter Particle Size Analyzer, expressed as cumulative volume percentof particles of size less than the channel diameter, plotted on alogarithmic scale from 0.1 to 100 microns. The distributioncorresponding to X _((A,B,C)) is shown as the bold line. Distributionscorresponding to ±1 SD (standard deviation), ±2 SD, and ±3 SD of themean at each channel diameter are provided (thin lines).

FIG. 14 is an enlargement of FIG. 13 in the small particle size range of0.1 to 1 microns.

FIG. 15 is an enlargement of FIG. 13 in the intermediate particle sizerange of 1 to 10 microns.

FIG. 16 is an enlargement of FIG. 13 in the large particle size range of10 to 100 microns.

FIG. 17 shows the particle size distribution of three samples (D, E, andF) of OMYA-Cal® USP-15-AZ calcium carbonate powder as measured on aCoulter Particle Size Analyzer, expressed as cumulative volume percentbetween each channel diameter, plotted on a logarithmic scale from 0.1to 100 microns.

FIG. 18 shows the particle size distribution of three samples (A, B, andC) of OMYA-Cal® USP-10-AZ calcium carbonate powder as measured on aCoulter Particle Size Analyzer, expressed as cumulative volume percentof particle size less than the channel diameter, plotted on alogarithmic scale from 0.1 to 100 microns.

FIG. 19 shows the particle size distribution corresponding to the meanat each channel diameter, designated X _((D,E,F)), of three samples (D,E, and F) of OMYA-Cal® USP-15-AZ calcium carbonate powder as measured ona Coulter Particle Size Analyzer, expressed as cumulative volume percentbetween each channel diameter, plotted on a logarithmic scale from 0.1to 100 microns.

FIG. 20 shows the particle size distribution corresponding to the meanat each channel diameter, designated X _((D,E,F)) of three samples (D,E, and F) of OMYA-Cal® USP-15-AZ calcium carbonate powder as measured ona Coulter Particle Size Analyzer, expressed as cumulative volume percentof particles smaller than the channel diameter, plotted on a logarithmicscale from 0.1 to 100 microns. The distribution corresponding to X_((D,E,F)) is shown as the bold line. Distributions corresponding to +1SD (standard deviation), +2 SD, and +3 SD of the mean at each channeldiameter are provided (thin lines).

FIG. 21 is an enlargement of FIG. 20 in the intermediate particle sizerang of 1 to 10 microns.

FIG. 22 shows the particle size distributions corresponding to X_((A,B,C)) and X _((D,E,F)) expressed as cumulative volume percentbetween each channel diameter, plotted on a logarithmic scale from 0.1to 100 microns.

FIG. 23 shows the particle, size distributions corresponding to X_((A,B,C)) and X _((D,E,F)) expressed as cumulative volume percent ofparticles of size less than the channel diameter, plotted on alogarithmic scale from 0.1 to 100 microns.

FIG. 24 shows the particle size distributions in the intermediate sizerange corresponding to X _((A,B,C)) and X _((D,E,F)) expressed ascumulative volume percent of particles of size less than the channeldiameter, plotted on a logarithmic scale from 1 to 10 microns. For X_((A,B,C)), distribution curve corresponding to −1SD, −2SD, and −3SD areprovided. For X _((D,E,F)) distribution curve corresponding to +1SD,+2SD, and +3SD are provided.

FIG. 25 shows the particles size distributions plotted on a logarithmicscale from 0.1 to 100 microns, expressed as volume percent between eachchannel diameter, for X _((A,B,C)), X _((D,E,F)) Sample G, and Sample H,corresponding to calcium carbonate powders having median particle sizesof 11.64, 16.13, 4.59, and 1.99 microns, respectively.

FIG. 26 shows particles size distributions in the large particle sizerange, expressed as cumulative volume of particles of size greater thanthe channel diameter for channel diameters between 10 micron and 100microns on a logarithmic scale, for X _((A,B,C)), Sample G, and SampleH.

FIG. 27 compares the calcium ion concentrations in the peritonealinterstitial fluid (ISF) as measured using an ultrafiltrate probe overvarious time intervals for rats fed diets comprising OMYA-Cal® USP-10-AZ(Omya, Inc.) calcium carbonate powder (group 1) or OMYA-Cal® USP-15-AZ(Omya, Inc.) calcium carbonate powder (group 2).

DETAILED DESCRIPTION OF THE INVENTION

In the following description of the invention, it is to be understoodthat the terms used have their ordinary and accustomed meanings in theart, unless otherwise specified. Reference to particle size herein willbe understood to refer to particle diameter, unless otherwise specified.Reference to particle size distributions herein will be understood torefer to the distributions (or histograms) of the particles on a volumebasis, unless otherwise specified. It is within the skill in the art toconvert the volume distributions to weight or number distributions, ifso desired. Reference to recommended daily intakes (DRIs) or adequateintakes (AIs) of calcium or other daily calcium doses specified herein,will be understood to refer to the amount of elemental calcium (asopposed to the amount of calcium carbonate), unless otherwise specified.“Elemental calcium” refers to the element Ca, in any oxidation state.Where a particle size is prefaced by the term “about,” it will beunderstood to include particle sizes which are within the range of errortypically associate with the measurement of particle size using thetechniques described herein.

By “enhanced absorption calcium carbonate” is meant a calcium carbonatepowder having an absorption efficiency of elemental calcium greater thanthe absorption efficiency of elemental calcium from a conventionalcalcium carbonate powder. By “conventional calcium carbonate powder” ismeant calcium carbonate powder from which about 30% of the elementalcalcium is absorbed in adults, and on which the daily adequate intakes(AIs) of 1,000 mg and 1,200 mg, set by the Institute of Medicine of theNational Academy of Sciences, are based. Conventional calcium carbonateincludes the calcium carbonate powder OMYA-Cal® USP-15-AZ (Omya, Inc.)described herein. In various embodiments, enhanced absorption calciumcarbonate will have an absorption efficiency at least 5% greater, atleast 7.5% greater, at least 10% greater, at least 12.5% greater, atleast 15% greater, or at least 20% greater than conventional calciumcarbonate. Put another way, the absorption efficiency of enhancedabsorption calcium carbonate in adults will be at least about 35%, atleast about 37.5%, at least about 40%, at least about 45%, or at leastabout 50%.

As used herein, the term “vitamin D” refers to broadly to vitamin D orany metabolite thereof, including without limitation, calciferol (D₂),cholecalciferol (D₃), calcidiol (25-hydroxy-vitamin D), calcitriol (1,25dihydroxy vitamin D₃), and the like.

As used herein, “OMYA-Cal® USP-10-AZ” refers to the commerciallyavailable (Omya, Inc.) pharmaceutical grade mined limestone calciumcarbonate powder (>99% CaCO₃) which has been ground to the particle sizedistribution of X _((A,B,C)) provided in Table 7 of Example 2, which isshown graphically in FIGS. 9-16, in particular in FIG. 12, andcharacterized by the distribution statistics provided in Table 8.OMYA-Cal® USP-10-AZ is further characterized in that it has had acidinsolubles removed.

The present invention is founded on the discovery that OMYA-Cal®USP-10-AZ, which has a median particle size of about 12 μm (microns),provides unexpectedly superior in vivo absorption efficiency andpositive calcium balance as compared to calcium carbonate powders ofother median particle sizes. The invention is not limited to the use ofthat OMYA-Cal® USP-10-AZ calcium carbonate powder, however. Rather,detailed analysis of the particle size distributions of this and othercalcium carbonate powders has yielded critical insights into theparameters affecting absorption of calcium carbonate in the intestine.Without wishing to be bound by any theory, it is believed that thesuperior in vivo utilization efficiency of the about 12 median particlesize OMYA-Cal® USP-10-AZ powder arises by virtue of its unique particlesize distribution. As shown by its particle size distributions, thiscalcium carbonate powder provides substantial amounts of small (e.g.,less than about 0.5 or 1 microns), intermediate (e.g. about 0.5 or 1microns to about 10 or 11 microns), and large particles (e.g., greaterthan about 10, greater than about 11 microns, or greater than about 12.5microns) which are believed to be differently utilized in the intestineto maximize net absorption, resulting in improved calcium balance.

Increasing net calcium absorption impacts bone calcium levels throughthe calcium homeostasis pathways. Calcium homeostasis in the body ismaintained through the cooperative effects of the calcium regulatorysystem, primarily comprising: (1) calcium absorption and loss throughthe intestine; (2) absorption and desorption of calcium from the bone;and (3) calcium excretion in the urine and re-absorption from thekidneys. The primary pathways of calcium regulation are shown in FIG. 1.The serum and extracellular fluid (ECF) levels of calcium in humans ismaintained in a relatively narrow range of about 2.25-2.5 mmol and thusmay be regarded as a relatively constant calcium pool. These levels aremaintained by the three principal regulatory components which act inconcert to maintain the serum calcium levels. As illustrated in FIG. 1,the amount of ingested calcium V_(i) is either lost through the feces,amount V_(f), or is absorbed through the intestine in an amount V_(a+).Endogenous calcium may also be lost from the calcium pool by desorptioninto the intestinal lumen, indicated by the quantity V_(a−). At timesthe loss of endogenous calcium V_(a−) may be substantial and may evenexceed the amount V_(a+). Accordingly, the term “net absorption” as usedherein refers to the total net change in calcium through the intestineor (V_(a+)−V_(a−)) which can be measured as (V_(i)−V_(f)). Net calciumabsorption efficiency is measured as (V_(i)−V_(f))/V_(i). The term“absorption” refers only to the amount V_(a+). The net change incalcium, commonly referred to as “calcium balance,” is defined asV_(i)−(V_(f)−V_(u)).

The absorption of calcium through the intestine may be regarded as thecontrolling factor of calcium balance whereas calcium loss from the boneand kidneys is up-regulated or down-regulated in response to intestinalcalcium absorption. Thus, in healthy individuals calcium loss from thebones V_(o−) is dependent on calcium absorption from the diet, withhigher levels of absorption resulting in increased bone ossificationV_(o+). Conversely, inadequate calcium absorption through the intestineresults in desorption of an amount of calcium V_(o−) from the bone tomaintain the serum levels. Similarly, the amount of calcium excreted inthe urine V_(u) is regulated by the re-absorption of calcium through therenal epithelial V_(k−) which proceeds through a mechanism similar toactive transport across the intestine, discussed below. The relevance ofeach of the three calcium regulatory mechanisms varies throughout lifeand thus presents different calcium demands at different times. Forexample, during early childhood the quantity V_(o+) will exceed V_(o−)resulting in net ossification of bone, highlighting the importance ofadequate calcium intake at young age. In lactating women andpost-menopausal women, however, the situation reverses, resulting in netcalcium flux out of the bone reserves. Thus, at all life stages, and inparticular in early life, lactation, and post-menopause, it is clearlydesirable to increase V_(a+).

There are two primary mechanisms of calcium absorption through theepithelial cells of the intestine: active transport (or facilitateddiffusion) and passive transport, both of which contribute to themagnitude of V_(a+). The first step in the active transport modelinvolves the transport of Ca²⁺ ions from the intestinal lumen throughthe transient receptor potential channel, vanilloid subfamily member 6(TRPV6) calcium channels of the intestinal epithelial cells, primarilyin the duodenum, jejunum, and ileum. Within the intestinal cells,intracellular diffusion of Ca²⁺ is facilitated by the calcium bindingprotein calbindin D_(9k) which binds two moles of calcium ion per mol ofprotein. The final step in the active transport model involves therelease of calcium into the plasma by the action of plasma membranecalcium ATPases (PMCAs) or by the action of a Na⁺/Ca²⁺ exchanger.Because active transport of calcium requires Ca²⁺ ions to be formed inthe intestinal lumen, there must be a sufficient quantity of such ionspresent to maximize active transcellular transport, although thismechanism becomes saturated and no additional benefit is attained athigh Ca²⁺ levels. The action of hydrochloric acid in the gut on calciumcarbonate produces Ca²⁺ ions at a rate proportional to the surface areaof the calcium carbonate particle. Therefore, small particles of calciumcarbonate react more rapidly to generate Ca²⁺ than do larger particles.To rapidly engage the active transport mechanism up to saturation, itwas theorized that an optimal calcium supplement must have a sufficientvolume of small calcium carbonate particles which will consume theavailable acid in the gut to yield Ca²⁺. In this regard, smallparticles, as that term is used herein, refers to particle sizestypically below about 1 micron.

The second mechanism by which calcium crosses the intestinal epitheliumis passive transport which involves the paracellular diffusion of bothCa²⁺ and particulate calcium carbonate between the cells. Passivetransport is believed to occur throughout the length of the intestine.This mechanism is independent of vitamin D status and regulated only byionic gradients across the gut as well as bulk fluid flow properties.While not wishing to be bound by any theory, it is believed that thepassive diffusion mechanism requires particles of specific particlessizes, including intermediate size particles, typically between about 1micron to about 10 microns.

Thus, the total absorption of calcium through the intestine is the sumof active and passive calcium absorption. Because the active mechanismis saturatable and is down-regulated as calcium intake increases, abovecalcium doses of about 120 mg the passive diffusion of calcium is thecontrolling determinant of net calcium absorption. Because passivetransport is not saturatable, net calcium absorption increases roughlylinearly with calcium intake at intake levels above about 120 mg,although in vivo rat studies indicate that with calcium carbonate aplateau is reached with calcium carbonate at intake levels above 450 mg.Pansu et al., “Solubility and Intestinal Transit Time Limit CalciumAbsorption in Rats,” J. Nutrition Vol. 123, No. 8, pp. 1396-1404 (1993).However, the efficiency of absorption, as a percentage of total calciumintake, is generally understood to be inversely related to calciumintake.

The presence of large particles, e.g., those having a size typicallygreater than about 10 microns, is also believed to be important to theimproved absorption of the inventive calcium carbonate supplements. Thelarger particles react slowly with hydrochloric acid and are notbelieved to be available for passive transport across the intestine byvirtue of their size. Accordingly, the residence time of large particlesin the gut will be longer than for smaller particles. As hydrochloricacid acts on the large particles over time, they are degraded to smallerparticles and calcium ions, thereby producing additional calcium informs and sizes sufficient to engage the active and passive transportmechanisms. It is theorized that the calcium in the larger particles cantherefore be metered out and presented to the intestinal epithelium overa longer period of time, essentially achieving a time-release calciumformulation. This is believed to be advantageous as it is known thatcalcium dosing regimens which are spread out throughout the day aresubstantially more effective than the delivery of the same dose in onebolus.

Ground limestone calcium carbonate powder having a median particle sizeof about 12 μm provides substantial volume of particles in each of thesmall, intermediate, and large particle ranges discussed above. Theprecise cutoffs for the various size ranges are derived empirically fromthe data in the Examples. Small particles are considered to be thosewhich react instantly or rapidly to form solubilized Ca⁺² cations in thestomach and thus do not have substantial residence times in theintestine as particulates. Typically, the size of such particles will beless than 1 micron, although in various embodiments of the invention the“small” particles may by less than about 2 microns, less than about 1.5microns, less than about 1 micron, less than about 0.5 microns, or lessthan about 0.25 microns in diameter. However, because solubilized Ca⁺²cations will be produced from calcium carbonate particles of all sizes,albeit at different rates, it is believed that sufficient calcium ionconcentration will be present to saturate the active transport mechanismwith most calcium carbonate sources regardless of the volume of smallparticles in the powder. Therefore, the precise volume of “small”particles is not considered essential to the practice of the invention,nevertheless it is believed to be advantageous to supply a substantialvolume of small particles as they may further serve to deplete or reducethe available supply of gastric acid and thereby retard the degradationof intermediate and large particles. In one embodiment, the presence ofsmall particle sizes of calcium carbonate powder is optional. In otherembodiments, the small particles will comprise at least about 1%, atleast about 2.5%, at least about 5%, at least about 7.5%, or at leastabout 9 or 10% of the total volume of calcium carbonate powder. In otherembodiments, the amount of small particles comprises from about 1 toabout 30%, from about 2.5 to about 25%, from about 5 to about 20%, fromabout 7.5 to about 10-15% by volume of the total volume of calciumcarbonate. The small particles may comprise the lower end of theparticle size distribution of a singular calcium carbonate source, suchas for example OMYA-Cal® USP-10-AZ, in which about 9% of the totalvolume of calcium carbonate has a particle size below about 1 micron, oralternatively may by supplied by a separate powder source.

The intermediate size particles are typically between about 1 and about11 microns, but in various embodiments the lower end of the intermediaterange may be about 0.25 microns, about 0.5 microns, or about 0.75microns, and the upper end of the intermediate range may be about 7.5microns, about 10 microns, about 12 microns, or about 15 microns. It isbelieved that these particle sizes are important for increasing oroptimizing the passive absorption of calcium. This conclusion followsfrom a comparison of the relative absorption efficiencies of OMYA-Cal®USP-10-AZ and OMYA-Cal® USP-15-AZ calcium carbonate powders in the ratmodel discussed in the Examples. As shown by the data in the Examples,the absorption efficiency and resulting calcium balance in rats issubstantially and unexpectedly higher in rats fed OMYA-Cal® USP-10-AZthan in rats fed OMYA-Cal® USP-15-AZ. The particle size distributions ofthese two powders is compared in FIG. 2, where X _((A,B,C)) representsthe average of three samples (A, B, and C) of OMYA-Cal® USP-10-AZ powderhaving a median particle size of about 12 microns and X _((D,E,F))represents the average of three samples (D, E, and F) of OMYA-Cal®USP-15-AZ powder having a median particle size of about 16 microns.Comparison of these distributions reveals that the volume of particlesof size greater than about 10 or 11 microns in the OMYA-Cal® USP-15-AZpowder is far greater than present in the OMYA-Cal® USP-10-AZ powder. Infact, the distribution curve for OMYA-Cal® USP-15-AZ subsumes that ofOMYA-Cal® USP-10-AZ above about 12 microns (the exact cross-over pointis at 11.83 microns). Thus, the superior results of OMYA-Cal® USP-10-AZpowder on absorption efficiency and calcium balance cannot be explainedsolely by the difference in particle size distributions in the regionabove 12 microns because the OMYA-Cal® USP-10-AZ powder provides lessvolume of particles at all sizes above 12 microns than provided byOMYA-Cal® USP-15-AZ. On the contrary, if this region of thedistribution, alone, were important it would be expected that the largermedian particle size material OMYA-Cal® USP-15-AZ would outperform.Similarly, below about 0.5 microns the distribution curves for these twocalcium carbonate powders are similar and below about 0.25 they areessentially identical. Accordingly, the superior results of OMYA-Cal®USP-10-AZ cannot be explained solely on the basis of the small particleseither.

It is therefore theorized that the difference in absorption efficiencyof OMYA-Cal® USP-10-AZ and OMYA-Cal® USP-15-AZ results from thedifferences seen in FIG. 2 between the particles of sizes in the rangeof about 0.5 or 1 micron to about 10 or 11 microns. Without wishing tobe bound be any particular theory, it is believed that the higher volumeof particles within this range in the OMYA-Cal® USP-10-AZ powder isimportant for enhancing or optimizing passive transport through theintestine (paracellular diffusion). Regardless of the correctness of thetheory, the results in the Examples establish the importance of particlesizes within the intermediate size range. Typically, the calciumcarbonate powders of the invention will comprise more than about 25% byvolume of particles within the intermediate size range. In variousembodiments, the calcium carbonate powder will comprise at least about26%, at least about 28%, at least about 30%, at least about 32%, atleast about 34%, at least about 36%, or at least about 38% by volumeparticles in the intermediate size range. The OMYA-Cal® USP-10-AZcalcium carbonate powder comprises about 38% by volume particles withinthe size range of about 1 micron to about 11 microns. The intermediateparticles may comprise a portion of one calcium carbonate powder sourceor may be provided from a separate calcium carbonate source.

The lower size cutoff of the “large” particles is not particularlycritical and may include particles larger than about 7.5, 10, 11, 12, orabout 15 microns. The volume of large particles will typically compriseat least about 40%, at least about 42.5%, at least about 45%, at leastabout 47.5%, or at least about 50% of the total volume of calciumcarbonate powder. Preferably, the volume of large particles will begreater than about 50%, or greater than about 52% of the total volume ofthe calcium carbonate powder, particularly in embodiments where thelarge particles are those having a particle size greater than about 10or 11 microns. The OMYA-Cal® USP-10-AZ calcium carbonate powdercomprises about 53% of the total volume at particle sizes greater thanabout 11 microns. It is believed that the presence of the largeparticles advantageously increases the residence time of the calciumcarbonate in the digestive system and thereby presents calcium to theintestine for active and passive absorption over a longer period of timethan achievable in the absence of such large particles.

The calcium carbonate powders meeting the criteria described herein maybe provided in any suitable form for delivery to humans or animals. Forexample, the calcium carbonate powders may be added to any food,beverage, chewable, candy, nutritional bar or the like. In variousembodiments, pharmaceuticals, nutraceuticals, functional foods, anddietary supplements are provided comprising the highly bioavailablecalcium carbonate powders of the invention.

Preferably, the calcium carbonate powders of the invention are providedin the form of calcium supplement tablets, such as, for example, thosedescribed in U.S. Pat. No. 7,198,653 to Lang et al., the disclosure ofwhich is hereby incorporated by reference. The tablets described in thatpatent will have a reduced tablet volume due in part to the uniqueprocessing parameters described therein. Further reduction in tabletvolume is achieved according to the present invention based on thediscovery that less enhanced absorption calcium carbonate is required tomeet the AIs as compared to conventional calcium carbonate. In fact,particular synergies in tablet size reduction will be obtained where thepreferred enhanced absorption calcium carbonate powders according to thepresent invention, which have a median particle diameter of about 12 μm,are incorporated into a highly compatible, high density granulationaccording to U.S. Pat. No. 7,198,653 and subsequently compressed into atablet.

Tablets according to the present invention include but are not limitedto molded tablets, chewable tablets, pellets, pills, triturates,hypodermic tablets, effervescent tablets, controlled-release tablets,and immediate release tablets. The calcium supplement tablet maycomprise any additional ingredients known to one skilled in the art,including pharmaceutically or nutraceutically acceptable excipients, forexample, carriers, diluents, disintegrants, lubricants, flavorants, andthe like.

The calcium supplement tablets may comprise any amount of the calciumcarbonate powders according to the invention, but will typicallycomprise from about 100 mg to about 4,000 mg of calcium carbonatepowder, preferably OMYA-Cal® USP-10-AZ (Omya, Inc.) calcium carbonatepowder. In various embodiments, the calcium supplement tablets willcomprise at least 200 mg, at least 300 mg, at least 400, at least 500,at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, atleast 1,000 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg,at least 1,500 mg, at least 1,600 mg, at least 1,700 mg, at least 1,800mg, at least 1,900 mg, or at least 2,000 mg of calcium carbonate powderaccording to the invention, preferably OMYA-Cal® USP-10-AZ (Omya, Inc.)calcium carbonate powder.

Preferably, the calcium supplements will also comprise vitamin D(including vitamin D metabolites). Typically, the supplement willcomprise at least about 200 I.U. (international units) of vitamin D,preferably, at least 300 I.U. of vitamin D, at least about 400 I.U. ofvitamin D, at least 500 I.U. of vitamin D, at least about 600 I.U. ofvitamin D, at least about 700 I.U. of vitamin D, at least about 800 I.U.of vitamin D, or at least about 900 I.U. of vitamin D, and may rangeupwards of (at least) about 1,000 I.U., about 2,000 I.U., about 2,500I.U., about 3,000 I.U. or about 3,500 I.U. of vitamin D. In some notableembodiments, the supplements will comprise about 400 I.U. of vitamin Dor about 800 I.U. of vitamin D per tablet or per dosage form. It iscontemplated that unexpectedly higher absorption efficiency will resultfrom the use of large doses of vitamin D including, without limitation,daily vitamin D doses of about 800 I.U. or 1,000 I.U. up to about 2,000I.U. or above. In the preferred practice of the invention, thesupplements will comprise vitamin D in the form of vitamin D₃ due to itssuperior ability to be stored in the human body as compared to the otherforms of vitamin D, including vitamin D₂. In some embodiments, thevitamin D may consist essentially of vitamin D₃ by which is meant thatany amounts of other vitamin D species (such as vitamin D₂), if present,should be of sufficiently low levels as to not have a measurable impacton calcium absorption as measured over a period of at least eight weeks.In other embodiments, the vitamin D will comprise at least about 75%,preferably at least about 85%, and more preferably, at least about 95%vitamin D₃ by weight. The vitamin D, particularly vitamin D₃, may beencapsulated in a gelatin matrix, or may be provided in an encapsulantthat is substantially free of gelatin (e.g., less than 1% gelatin) orfree of gelatin, such as, without limitation, a microcrystallinecellulose matrix.

The supplements of the invention may comprise one or more calciumcarbonate powders, at least one of which meets the particle sizedistribution characteristics defined herein. Thus, the addition of othercalcium carbonate powders, or other powders of calcium salts, is notcontemplated to be deleterious to the practice of the invention providedthat at least one calcium carbonate powder is present which satisfiesthe particle size distribution criteria discussed herein, including forexample OMYA-Cal® USP-10-AZ.

Similarly, the invention is not limited to the use of a singular powderwhich meets the specified particle size limitations, but rather embracesmixtures of different calcium carbonate powders provided that theaggregate provides sufficient volume of small, intermediate, and largeparticles as described herein. Thus it is contemplated that two powders(or more) of different median particle size may be combined to provide asingular powder meeting the particle size distribution requirements forenhanced absorption.

In one embodiment, the calcium carbonate in the supplements of theinvention comprises, consists essentially of, or consists of a singularcalcium carbonate powder meeting the particle size limitations describedherein, including without limitation, OMYA-Cal® USP-10-AZ calciumcarbonate powder, and optionally one or more pharmaceutically ornutraceutically acceptable excipients, and optionally vitamin D or anyother absorption enhancing agent. By “consists essentially of” is meantthat any amounts of other calcium carbonate powder, such as conventionalcalcium carbonate powder, which would diminish the enhanced absorptionof the inventive calcium carbonate is excluded. In one embodiment, thepresence of additional calcium carbonate powder, such as conventionalcalcium carbonate powder, is excluded if the presence of such powder, inthe aggregate, would result in a net decrease in the volume of particlesin the intermediate size range.

It is further contemplated that other calcium sources may optionally beincluded with the calcium carbonate powders of the invention. However,it is preferred that such other calcium sources also exhibit highbioavailability (i.e., higher absorption than conventional calciumcarbonate). In this regard, special mention may be made of the calciumcitrate malate salts described in U.S. Pat. No. 5,128,374 toKochanowski; U.S. Pat. No. 5,186,965 to Fox et al.; U.S. Pat. No.5,314,919 to Jacobs; U.S. Pat. No. 5,468,506 to Andon; and U.S. Pat. No.6,080,431 to Andon et al., the disclosures of which are herebyincorporated by reference herein. Accordingly, one embodiment of theinvention comprises a composition comprising enhanced absorption calciumcarbonate and calcium citrate malate, which composition may be includedin a tablet, or any other delivery vehicle known in the art, includingthose described herein.

The invention provides methods for increasing calcium absorption or netcalcium absorption in a human or mammal comprising administering to thehuman or mammal any of the inventive calcium carbonate forms definedherein. Preferably, the calcium form has a particle size distributionsimilar to (±3SD), approximately the same as (±2SD), substantiallyidentical to (±1SD), or identical to the particle size distribution of X_((A,B,C)) across the entire range of particle sizes. In otherembodiments, the enhanced absorption calcium carbonate powders have aparticle size distribution similar to, approximately the same as,substantially identical to, or identical to the particle sizedistribution of X _((A,B,C)) across the range of intermediate particles(e.g., about 0.25, 0.5, 0.75, or 1 microns to about 10, 11 or 12.5microns) and optionally similar to, approximately the same as,substantially identical to, or identical to the particle sizedistribution of X _((A,B,C)) across the range of small and/or largeparticle sizes or any portion thereof.

In preferred embodiments of the inventive method, the calcium carbonatepowder is delivered in conjunction with vitamin D, preferably at a levelof at least 200 I.U. of vitamin D, and more preferably, at least about400 I.U. of vitamin D per dose. The method embraces once-a-day dosingregimens as well as multiple dosing regimens. Typically, the dosingregimen will provide at least 300 mg, at least 350 mg, at least 400 mg,at least 500 Trig, at least 600 mg, at least 700 mg, at least 1,000 mg,at least 1,200 mg, at least 1,300 mg, at least 1,500 mg, or at leastabout 1,800 mg of elemental calcium daily. In preferred embodiments, themethods of the invention achieve an absorption efficiency at least about5% greater, at least 7.5% or greater, preferably at least about 10%greater, more preferably at least about 15% greater, and more preferredstill, at least 20% or greater than achievable with otherwise comparableformulations of any other known calcium carbonate powder (i.e.,“conventional calcium carbonate powder”), including those having amedian particle size of 2, 5, or 16 microns as described herein. In apreferred embodiment, the method of the invention comprisesadministering to an individual in need thereof the calcium carbonatepowder OMYA-Cal® USP-10-AZ (Omya, Inc.), preferably in a dose of atleast about 600 mg daily up to about 3,500 mg or more daily, and atleast 200 I.U., preferably at least 400 I.U., of vitamin D up to about2,500 I.U., daily.

It is known that adequate calcium ingestion during childhood is criticalfor developing peak skeletal mass. For example, it has been estimatedthat 40% of the lifetime bone mass is accumulated during adolescence.See Greer et al., “Optimizing Bone Health and Calcium Intakes ofInfants, Children, and Adolescents,” Pediatrics, Vol. 117 No. 2 Feb.2006, pp. 578-585. Building healthy bones during childhood will reducefractures and may partially offset future calcium demands, therebyserving as a preventative measure against osteoporosis in later life.See Institute of Medicine, Food and Nutrition Board. Dietary ReferenceIntakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride.Washington, D.C.: National Academy Press; 1997, the disclosure of whichis hereby incorporated by reference. Accordingly, one embodiment of theinvention provides a method of building or strengthening bones inpre-adolescents or adolescents humans or mammals comprisingadministering daily, preferably chronically or for a period of at leasteight weeks, to a pre-adolescent or adolescent individual (male orfemale) any of the highly bioavailable calcium carbonate powders of theinvention, including but not limited to OMYA-Cal® USP-10-AZ, and vitaminD. Preferably, at least about 1,500 mg to about 4,000 mg of calciumcarbonate is administered daily and at least 400 I.U., at least 800I.U., or at least 1,000 I.U. up to about 2,500 I.U. of vitamin D isadministered daily. The compositions and methods of the invention arealso contemplated to be useful for preventing bone fractures, improvinghealing time of bone fractures, and improving bone strength in boneswhich have been fractured.

The highly bioavailable calcium carbonate powders of the invention,including but not limited to OMYA-Cal® USP-10-AZ are contemplated to beuseful for preventing, treating, reversing, and/or ameliorating boneloss associated with osteoporosis, particularly in combination withvitamin D. Accordingly, the invention provides in one embodiment amethod of preventing, treating, reversing, and/or ameliorating bone losscomprising administering to a patient in need thereof (i.e., a patientsuffering from osteoporosis or at risk of developing osteoporosis) aneffective amount of any of the calcium carbonate powders of theinvention, such as OMYA-Cal® USP-10-AZ, for a time sufficient toprevent, treat, reverse, and/or ameliorate bone loss. The term“effective amount” refers to a dosage sufficient to provide therecommended daily intake of elemental calcium. The time sufficient toprevent, treat, reverse, and/or ameliorate bone loss is not contemplatedto be particularly limited and includes, for example, dailyadministration for at least two weeks, preferably at least eight weeks,and more preferably chronic administration.

It is contemplated that the methods of the invention will constitute auseful complement to pharmaceutical intervention or, ideally, as areplacement for osteoporosis drugs such as bisphosphonates. In oneembodiment, a pharmaceutical composition comprises a pharmaceuticallyeffective amount of any of the calcium carbonate materials havingenhanced bioavailablity described herein and a pharmaceuticallyeffective amount of a bisphosphonate osteoporosis drug. In anotherembodiment, the pharmaceutically effective amounts of calcium carbonateand bisphosphonate are delivered to a patient in need thereof (e.g., apatient suffering from osteoporosis) seriatim. Thus, a method fortreating osteoporosis comprises administering to a patient,simultaneously or seriatim, a pharmaceutically effective amount of anyof the calcium carbonate materials having enhanced bioavailabilitydescribed herein and a pharmaceutically effective amount of abisphosphonate osteoporosis drug.

In this context, the term “pharmaceutically effective amount” refers toan amount sufficient to prevent, reduce, reverse, and/or ameliorate boneloss associated with osteoporosis. In the case of calcium carbonate, thepharmaceutically effective amount will typically be at least about 100mg or at least about 200 mg, more typically at least about 300 mg, andpreferably at least about 400 mg, and more preferably, at least about500 mg, and more preferred still, at least about 600 mg of calciumcarbonate per dosage form. On a daily basis, a pharmaceuticallyeffective amount” of calcium carbonate will be from about 100 to about3,500 mg/day, from about 200 to about 3,000 mg/day, from about 300 toabout 2,500 mg/day, from about 400 to about 2,500 mg/day, from about 500to about 2,500 mg/day, or from about 600 to about 2,500 mg/day. Ideally,the pharmaceutically effective amount of calcium carbonate will be suchthat typically at least about 600, more typically at least about 700,preferably at least about 800, more preferably at least about 900, andmore preferred still at least about 1,000 mg of elemental calcium isdelivered per dosage form or per day.

The “pharmaceutically effective amount” of calcium carbonate willoptimally delivery sufficient elemental calcium to at least meet the AIof 1,000 mg/day in adults (ages 19 to 50) or 1,200 mg/day for those over50, but will preferably be even higher and will include amounts up toabout 1,800 mg/day, or even 2,500 mg/day of elemental calcium. Thepharmaceutically effective amount of bisphosphonate will of coursedepend on the particular bisphosphonate, but will typically range fromabout 0.1 to about 500 mg. On a daily basis, the pharmaceuticallyeffective amount will usually range from about 0.5 to about 25 mg, fromabout 0.75 to about 20 mg, from about 1 to about 17 mg, from about 1.5to about 15 mg, or from about 2 to about 10 mg per day. Exemplary,pharmaceutically effective amounts of bisphosphate include about 0.5, 1,1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12.5, or about 15 mg per day, eachbeing understood to be a distinct embodiment of the invention. Thus,individual dosage forms for daily administration will typically comprisethe foregoing amounts of bisphosphonate or may be formulated as twicedaily or thrice daily forms which collectively provide the foregoingamounts on a daily basis (for example, a twice daily dosage may compriseexactly or approximately half of the foregoing effective amounts).Preferably, the daily effective amount is delivered as a single dosageadministered once daily. On a weekly basis, the pharmaceuticallyeffective amount of bisphosphonate will usually range from about 5 toabout 200 mg, from about 10 to about 150 mg, from about 20 to about 100mg, from about 30 to about 80 mg, or from about 35 to about 75 mg perweek provided as one or more doses. Exemplary, pharmaceuticallyeffective amounts of bisphosphate include about 20, 25, 30, 35, 40, 45,50, 55, 60, 65, or about 75 mg per week, each being understood to be adistinct embodiment of the invention. Thus, individual dosage forms forweekly administration will typically comprise the foregoing amounts ofbisphosphonate, or dosage forms may be formulated to provide a dosageregimen which collectively provides these weekly effective amounts whenadministered once, twice, or thrice daily, every two days, twice weekly,once weekly, or the like. Preferably, the effective amount, on a weeklybasis, is delivery as a single dosage once a week. The pharmaceuticallyeffective amount of bisphosphonate may also be delivered as a monthlydosage which will typically range from about 20 to about 800 mg, fromabout 40 to about 600 mg, from about 80 to about 400 mg, from about 120to about 350 mg, or from about 140 to about 300 mg per month provided asone or more doses. Exemplary, pharmaceutically effective amounts ofbisphosphate include about 100, 125, 150, 175, 200, 225, 250, 275, 300,325 or about 350 mg per month, each being understood to be a distinctembodiment of the invention. The effective amount on a monthly basis maybe delivered daily, weekly, bi-weekly, once-a-month, or the like, whereeach administration is formulated to deliver equal amounts ofbisphosphante which collectively total to the monthly effective amount.Preferably, the effective amount, on a monthly basis, is delivery as asingle dosage once a month.

The osteoporosis treatment regimens preferably comprise theadministration of a pharmaceutically effective amount of calciumcarbonate on a daily basis, more preferably, on a twice-daily basis, andmore preferred still at a plurality of intervals through a day, e.g.three times daily, four times daily, hourly, every two hours, etc. Whileit is contemplated that the benefits of the invention will be most fullyrealized with multiple daily administrations of calcium carbonate, itmay be advantageous to administer calcium carbonate only once daily ortwice daily due known difficulties with patient compliance in multi-doseregimens. The bisphosphonate will typically be administered once daily,once weekly or once monthly. When delivered once daily, the calciumcarbonate and bisphosphonante may be administered together (e.g., in thesame dosage form or in separate dosage forms taken together) oradministered seriatim, in either order and with any period of timebetween each administration. It has been suggested that calcium may, tosome extent, interfere with absorption of bisphosphonates. Therefore, itmay be desirable to provide a daily regimen comprising, for example,taking calcium carbonate in the morning and bisphosphonate in theevening, or vice versa, or one before a meal and one after, etc.However, the advantages of high patient compliance with single doseswill likely offset any reduction in bisphosphonate absorption.Therefore, in a preferred embodiment, the effective amounts of calciumcarbonate and bisphosphonate are delivered together, preferably in asingle dosage form.

Suitable bisphosphonates include, without limitation, thosebisphosphonates suitable for oral delivery, for example, alendronate(Fosamax®); risedronate (Actonel®); ibandronate (Boniva®) and the like,as well as injectable bisphosphonates, such as etidronate (Didronel®),pamidronate (Aredia®), zoledronate (Zometa®) and the like. Preferredbisphosphonates according to the invention are alendronate, risedronate,and ibandronate.

The pharmaceutical compositions and dosing regimens may also includevitamin D in any dose described herein. Preferably, at least 200 I.U. ofvitamin D are delivered daily and more preferably at least 400 I.U., 800I.U., or 1,000 I.U. daily of vitamin D. In other embodiments, dailydoses of vitamin D may be up to about 2,000 I.U. or more, includingexemplary ranges of about 200 to about 2,000 I.U., about 400 to about1,750 I.U., about 600 to about 1,500 I.U. or about 1,000 I.U. daily.

In a currently preferred embodiment, the bisphosphonate is alendronate,and the pharmaceutically effective dose is typically about 5 to about 15mg, preferably, about 6 to about 14 mg, more preferably about 7 to about13 mg, and more preferred still about 8 to about 12 mg per day. Superiorresults are contemplated where the dosage of alendronate is betweenabout 9 and about 11 mg daily or about 10 mg daily. The pharmaceuticallyeffective amounts for weekly or monthly administration are contemplatedto be approximately the daily effective amount multiplied by the dosinginterval. That is, a weekly effective amount will be, for example,approximately seven times the daily amount and a monthly effectiveamount will be approximately 30 times the daily effective amount. It iscontemplated that a weekly dose of about 50 to about 80 mg/week or about65 to about 75 mg/week will be particularly useful. Of course, any ofthe daily, weekly, or monthly pharmaceutically effective amounts ofbisphosphonate described elsewhere herein are equally applicable to thisembodiment.

In another currently preferred embodiment, the bisphosphonate isrisedronate, and the pharmaceutically effective dose is typically about1 to about 10 mg, preferably, about 1.5 to about 9 mg, more preferablyabout 2 to about 8 mg, and more preferred still about 2.5 to about 7 mgper day. Superior results are contemplated where the dosage ofalendronate is between about 3 and about 6 mg daily, 4 and about 6 mgdaily, or about 5 mg daily. The pharmaceutically effective amounts forweekly or monthly administration are contemplated to be approximatelythe daily effective amount multiplied by the dosing interval. It iscontemplated that a pharmaceutically effective does of about 25 to about45 mg/week or about 30 to about 40 mg/week will be particularly useful.The daily, weekly, or monthly pharmaceutically effective amounts ofbisphosphonate described elsewhere herein are equally applicable to thisembodiment.

In an additional embodiment, the bisphosphonate is ibandronate, and thepharmaceutically effective dose is typically about 0.5 to about 6 mg,preferably, about 1 to about 5 mg, more preferably about 1.5 to about 4mg, and more preferred still about 2 to about 3 mg per day. Superiorresults are contemplated where the dosage of ibandronate is about 2.5 mgdaily. The pharmaceutically effective amounts for weekly or monthlyadministration are contemplated to be approximately the daily effectiveamount multiplied by the dosing interval. It is contemplated that apharmaceutically effective dose of ibandronate of about 100 to about 200mg/month or about 125 to about 175 mg/month, or about 150 mg/month willbe particularly useful. The daily, weekly, or monthly pharmaceuticallyeffective amounts of bisphosphonate described elsewhere herein areequally applicable to this embodiment.

In one embodiment, a single dosage form, i.e., a tablet, capsule, pill,etc., comprises an effective amount of OMYA-Cal® USP-10-AZ calciumcarbonate (or any other highly bioavailable calcium carbonate describedherein) and a pharmaceutically effective amount of a bisphosphonate,preferably selected from the group consisting of alendronate,risedronate, and ibandronate. In another embodiment, a single dosageform is provided comprising from about from 100 to about 1,000 mg ofOMYA-Cal® USP-10-AZ calcium carbonate and about 5 to about 15 mg ofalendronate, or about 1 to about 10 mg risedronate, or about 0.5 toabout 6 mg ibandronate, or combinations thereof. Preferably, the dosageform also includes vitamin D in any amount described herein. The dosagefrom may optionally include one or more pharmaceutically acceptableexcipients.

In one embodiment contemplated to be especially useful, a compositionfor treating osteoporosis will comprises about 5 mg, 10 mg, 35 mg, 40mg, or 70 mg of alendronate or about 5 mg to about 35 mg of risedronate,or about 2.5 mg to about 100 mg or 150 mg of ibandronate, and aneffective amount of OMYA-Cal® USP-10-AZ calcium carbonate, or any othercalcium carbonate powder described herein, and vitamin D, andoptionally, one or more pharmaceutically acceptable excipients. Theterms alendronate, risedronate, and ibandronate are intended to includepharmaceutically acceptable salts thereof, including alendronate sodium,risedronate sodium, ibandronate sodium, and the like.

In another embodiment, the calcium carbonate powders according to theinvention are included in a multi-vitamin comprising one or more activeagents selected from the group consisting of vitamin A, vitamin C,vitamin D, vitamin E, vitamin K, thiamin, riboflavin, niacin, vitaminB₆, folic acid, vitamin B₁₂, biotin, pantothenic acid, calcium,phosphorus, iodine, magnesium, zinc, selenium, copper, manganese,chromium, molybdenum, chloride, potassium, boron, nickel, silicon,vanadium, lutein, lycopene, iron, tin, ginseng root, and ginkgo bilobaleaf, to name a few.

The multi-vitamin will typically comprise from about 10 mg to about2,000 mg, more typically from about 25 mg to about 1,000 mg, preferablyfrom about 50 mg to about 750 mg, and more preferred still, from about100 mg to about 500 mg of calcium carbonate according to the invention,preferably OMYA-Cal® USP-10-AZ calcium carbonate powder. In oneembodiment, the multi-vitamin will comprise about 385-420 mg of calciumcarbonate and will preferably be capable of delivering at least about 50mg, at least about 55 mg, at least about 60 mg, at least about 70 mg, atleast about 80 mg, or at least about 90 mg of absorbable elementalcalcium, by which is meant that the specified dose of elemental calciumis actually absorbed through the intestine based on a populationaverage, rather than on an individual basis. In another embodiment, themulti-vitamin will comprise about 420-470 mg of calcium carbonate andwill preferably be capable of delivering at least about 60 mg, at leastabout 65 mg, at least about 70 mg, at least about 75 mg, at least about80 mg, or at least about 85 mg of absorbable elemental calcium. Inanother embodiment, the multi-vitamin will comprise about 470-520 mg ofcalcium carbonate and will preferably be capable of delivering at leastabout 70 mg, at least about 75 mg, at least about 80 mg, at least about85 mg, at least about 90 mg, or at least about 95 mg, or at least about100 mg of absorbable elemental calcium.

The multi-vitamin may comprise one or more vitamins selected from thegroup consisting of:

-   -   between 1 and about 35,00010 of vitamin A;    -   between 1 and about 1,000 mg of vitamin C;    -   between 1 and about 4,000 IU of vitamin D;    -   between 1 and about 450 IU of vitamin E;    -   between 1 and about 250 mcg of vitamin K;    -   between 1 and about 15 mg of vitamin B-1 (thiamin);    -   between 1 and about 17 mg of vitamin B-2 (riboflavin);    -   between 1 and about 200 mg of vitamin B-3 (niacin);    -   between 1 and about 100 mg of vitamin B-5 (pantothenic acid);    -   between 1 and about 30 mg of vitamin B-6 (pyridoxine);    -   between 1 and about 4,000 mcg of vitamin B-9 (folic acid);    -   between 1 and about 250 mcg of vitamin B-12 (cobalamin); and    -   between 1 and about 1,000 mcg of vitamin H (biotin);    -   and combinations thereof.

The multi-vitamin may also comprise one or more minerals selected fromthe group consisting of:

-   -   between 1 and about 180 mg of iron;    -   between 1 and about 1,100 mg of phosphorous;    -   between 1 and about 1,500 mcg of iodine;    -   between 1 and about 4,000 mg of magnesium;    -   between 1 and about 150 mg of zinc;    -   between 1 and about 600 mcg of selenium;    -   between 1 and about 20 mg of copper;    -   between 1 and about 20 mg of manganese;    -   between 1 and about 2,000 meg of chromium; and between 1 and        about 750 mcg of molybdenum;    -   between 0.001 and about 0.1 mg of tin;    -   between 1 and about 100 mcg of vanadium;    -   between 0.5 and 50 mcg of nickel;    -   and combinations thereof.

The multi-vitamin tablets may be of any volume, but are preferably sizedto correspond to any of the tablet volumes or ranges of volumesspecified herein, and in particular the volumes provided in Example 3.

Based on the discovery that the inventive calcium carbonate powders(“enhanced absorption calcium carbonate”) have increasedbioavailability, less enhanced absorption calcium carbonate, on a weightor volume basis, will be required to provide the same level ofabsorbable elemental calcium (i.e., the average amount actually absorbedthrough the intestine, as described herein) as provided by conventionalcalcium carbonate powders. Therefore, it will be seen that it ispossible to reformulate an existing calcium supplement tablet (chewableor swallowable) by replacing the conventional calcium carbonate in suchproduct with the enhanced absorption calcium carbonate according to theinvention, e.g., on an equal weight basis, to boost the amount ofabsorbable elemental calcium delivered by the product. In someembodiments, the amount of absorbable elemental calcium may be increasedby at least about 5%, at least about 7.5%, at least about 10%, at leastabout 15%, at least about 20%, or more without increasing the size ofthe tablet. It is contemplated that the boost in absorbable elementalcalcium will provide a significant advantage in the marketplace asconsumers are desirous of obtaining the maximum dosage of elementalcalcium possible per tablet, particularly since the size of the tabletdoes not need to be increased to achieve the enhancement in absorbableelemental calcium.

Thus, in one embodiment of the invention, a method for reformulating acalcium supplement is provided comprising: (i) providing a calciumsupplement comprising calcium carbonate powder (“first calcium carbonatepowder”); and (2) reformulating said calcium supplement by replacing allor a portion of said first calcium carbonate powder in said calciumsupplement with enhanced absorption calcium carbonate powder having anabsorption efficiency greater than that of said first calcium carbonatepowder. Preferably, the enhanced absorption calcium carbonate will havean absorption efficiency at least about 5% greater, at least about 7.5%greater, at least about 10% greater, at least about 15% greater, or atleast about 20% greater than said first calcium carbonate powder. By“first calcium carbonate powder” is meant a calcium carbonate powderpreviously included in said calcium supplement, preferably but notnecessarily, a commercially marketed calcium supplement, prior to thestep of reformulating. In one embodiment, the step of reformulating willcomprise replacing some or all of a first calcium carbonate powderhaving a median particle size greater than 15 μm or less than 10 μm withany of the enhanced absorption calcium carbonate powders according tothe invention, in particular with OMYA-Cal® USP-10-AZ calcium carbonatepowder. In another embodiment, the step of reformulating will comprisereplacing some or all of a first calcium carbonate powder comprisingOMYA-Cal® USP-15-AZ (Omya, Inc.), a ground mined limestone calciumcarbonate powder having a median particle size of about 16 μm (typicalrange ˜15 to about ˜17 due to error of measurement), with an enhancedabsorption calcium carbonate powder, such as OMYA-Cal® USP-10-AZ calciumcarbonate powder. In one embodiment, the first calcium carbonate powderwill be replaced by the enhanced absorption calcium carbonate on anequal weight basis, and preferably all of the first calcium carbonatepowder will be replaced. The size of the calcium supplement may remainthe same, or substantially the same (e.g., with ±5%, or ±2.5% of theoriginal volume), or may even advantageously be reduced withoutdecreasing, while preferably increasing, the amount of absorbableelemental calcium as compared to the supplement prior to reformulation.

In a related embodiment, the calcium supplement may be reformulatedaccording to the preceding method by removing a portion or all of thefirst calcium carbonate powder, but replacing therewith an amount ofenhanced absorption calcium carbonate that is less than the amount ofsaid first calcium carbonate powder removed on a weight basis. In thismanner, a tablet which is smaller than the original supplement can bemade which nevertheless provides the same, or ever greater, absorbableelemental calcium per tablet. In accordance with this embodiment, it maybe desirable to replace 6, 7, or 8 parts by weight of the first calciumcarbonate powder with 5 parts by weight of enhanced absorption calciumcarbonate according to the invention.

In another embodiment, a method is provided comprising: (i) providing acalcium supplement marketed under a brand name, said calcium supplementcomprising calcium carbonate powder (“first calcium carbonate powder”);(2) reformulating said calcium supplement by replacing all or a portionof said first calcium carbonate powder in said calcium supplement withenhanced absorption calcium carbonate powder having an absorptionefficiency greater than that of said first calcium carbonate powder; and(3) marketing said reformulated calcium supplement under said same brandname. By “brand name” is meant, without limitation, a trademark, tradename, or the like (e.g., “Caltrate®”) and by “same brand name” is meantthat at least one trademark, trade name, etc. will be in common betweenthe original and reformulated products. This method may find particularutility for any brand of calcium supplement which is widely recognizedin the marketplace by consumers. For example, a manufacturer may notwish to substantially change the tablet size, calcium carbonate content,etc., due to the existing goodwill associated with an establishedcommercial product, but nevertheless may wish to reformulate the productand market it under the same brand name but with an “improvedabsorption” claim or the like. It is contemplated that sales of calciumsupplements under an existing brand name will be improved by the abilityto make such a claim, regardless of whether the tablets remainsubstantially the same size, or decrease, after reformulation.

Special mention may be made of the use of the foregoing methods toreformulate any calcium supplement comprising about 600 mg(±manufacturing tolerances or customary overages) of elemental calcium,as this is a standard dosage form for commercially available calciumsupplements because such tablets, when taken twice daily, provide theAdequate Intake (AI) of 1,200 mg elemental calcium set by the Instituteof Medicine of the National Academy of Sciences. However, in embodimentswhere all of the conventional calcium carbonate in such a calciumsupplement is replaced with enhanced absorption calcium carbonate havingan absorption efficiency of about 50%, it is surprisingly seen that thereformulated tablet will provide the AI of 1,000 mg of elemental calciumwhen taken once daily. Thus, the reformulated product will have theadvantage of being flexibly marketed as a twice-a-day tablet (e.g., toachieve AIs of 1,200 mg or 1,300 mg) or as a once-a-day tablet toachieve the AI of 1,000 mg recommend for the large population segmentbetween 19 and 50 years old.

The ability to retain or even boost the amount of absorbable elementalcalcium while removing or keeping constant the amount of calciumcarbonate in a tablet is contemplated to also find utility informulating or reformulating (e.g., according to the foregoing methods)chewable calcium supplement or chewable antacids comprising calciumcarbonate. One drawback to such chewable products is the perception ofchalky taste commonly associated therewith. Since less enhancedabsorption calcium is required on a weight basis to achieve the samelevel of absorbable elemental calcium as compared to a conventionalcalcium carbonate powder, more volume in a tablet is thus provided forthe inclusion of additional ingredients which can serve to mask thechalky taste, such as sweeteners (natural or artificial), flavorants,and components which modify the texture of the product in the mouthduring chewing. Thus, it is possible to formulate superior tastingchewable tablets comprising enhanced absorption calcium carbonatewithout changing the size of the tablet, and preferably with a reductionin tablet size. A chewable calcium supplement or antacid according tothe invention will typically comprise from about 2,000 mg to about 4,000mg of enhanced absorption calcium carbonate, more typically betweenabout 2,500 mg and about 3,500 mg, including a representative embodimentof a chewable tablet comprising about 3,000 mg of enhanced absorptioncalcium carbonate and preferably further including vitamin D in anyamount specified herein, including without limitation, about 1,000 I.U.per tablet. The superior tasting chewable tablets will have a reducedperception of chalkiness, as determined by consumer testing or expertevaluation, as compared to a chewable tablet of the identical size whichdelivers substantially the same amount of absorbable elemental calciumprovided by conventional calcium carbonate.

In one embodiment of the invention, a product is provided comprising:(a) a container comprising a plurality of tablets for dietary calciumsupplementation, the tablets comprising an amount of enhanced absorptioncalcium carbonate powder sufficient to provide the AI of 1,000, 1,200,or 1,300 mg and vitamin D; and (b) instructions on the product labeling,packaging, or insert, for the use of the tablets in a single daily doseto achieve a full day requirement of calcium.

In another embodiment of the invention, a method is provided forincreasing the absorbable calcium content of a calcium carbonatecontaining multi-vitamin product in tablet from, without requiring achange the size of the tablet, comprising replacing a portion or all ofthe conventional calcium carbonate in said multi-vitamin tablet with anyof the inventive enhanced absorption calcium carbonate powders accordingto the invention, on an equal weight basis. In another embodiment of theinvention, a method is provided for reducing the size (volume) of aconventional calcium carbonate containing multi-vitamin product, withoutsubstantially changing the amount (e.g., within ±5%) of absorbableelemental calcium in the product, comprising replacing a portion or allof the calcium carbonate in said multi-vitamin with any of the inventiveenhanced absorption calcium carbonate powders according to theinvention, on an less than equal weight basis, preferably by removingabout 6-7 parts conventional calcium carbonate for each 5 parts enhancedabsorption calcium carbonate added.

In one interesting variant, the calcium carbonate powder is added tochocolate or chocolate compound coating as described in U.S. patentapplication Ser. No. 11/437,371, the disclosure of which is herebyincorporated by reference. Calcium fortified chocolate or chocolatecompounds coating is provided by substituting the calcium powdersdescribed herein for those of U.S. patent application Ser. No.11/437,371. Advantageously, preferred calcium carbonate powders of thepresent invention will have median or mean particle sizes suited toformulating the composition of U.S. patent application Ser. No.11/437,371. Preferred compositions according to this variant willcomprise at least about 10%, at least about 15%, at least about 20%, orat least about 25% by weight calcium carbonate, preferably OMYA-Cal®USP-10-AZ calcium carbonate powder, dispersed homogenously in achocolate or chocolate compound coating matrix, and optionally willcomprise vitamin D wherein each dosage size or serving size may compriseany amount of vitamin D specified herein.

The calcium carbonate powders may also be used to enhance the dietarycalcium content of bread products using the methods and ingredientsdescribed in U.S. Pat. Nos. 7,166,313 and 7,169,417 to Dibble et al.,and U.S. patent application Ser. Nos. 11/462,560, and 11/462,581, thedisclosures of which are hereby incorporated by reference. In onevariant, a calcium additive comprises OMYA-Cal® USP-10-AZ calciumcarbonate powder and citric acid in an intimate admixture in the ratiosdescribed in U.S. patent application Ser. Nos. 11/462,560 and11/462,581, and optionally vitamin D. These additives will be useful forenriching the calcium content of baked goods, and the like. Oneembodiment of the present invention therefore is a composition forbaking comprising a mixture of dough ingredients and a calcium additivecomprising and intimate admixture of OMYA-Cal® USP-10-AZ or any suitablecalcium carbonate according to the invention. In one embodiment, a bakedproduct, particularly a leavened bread product, such as a hamburger bun,comprising OMYA-Cal® USP-10-AZ in any of the amounts described in U.S.Pat. Nos. 7,166,313 and 7,169,417 to Dibble et al., and U.S. patentapplication Ser. Nos. 11/462,560, and 11/462,581 is provided.

In other embodiments, the powders may be delivered neat, as slurries,tube-fed diets, or the like.

EXAMPLES

In the following examples, the following designations are used to referto the specified commercially available calcium carbonate powders:

“Calcium Carbonate[16]” refers to the calcium carbonate powder having amedian particle size of about 16 microns available from OMYA, Inc. underthe trademark OMYA-Cal® USP-15-AZ. OMYA-Cal® USP-15-AZ is ground minedlimestone calcium carbonate.

“Calcium Carbonate[12]” refers to the calcium carbonate powder having amedian particle size of about 12 microns available from OMYA, Inc. underthe trademark OMYA-Cal® USP-10-AZ. OMYA-Cal® USP-10-AZ is ground minedlimestone calcium carbonate.

“Calcium Carbonate[5]” refers to the calcium carbonate powder having amedian particle size of 4.6 microns available from OMYA, Inc. under thedesignation V-70. The V-70 product is a precipitated calcium carbonatepowder comprising rose-shaped crystals.

“Calcium Carbonate[2]” refers to the calcium carbonate powder having amedian particle size of about 2 microns available from MineralsTechnologies Inc. under the trademark ALBAGLOS PCC® (advertised ashaving a particle size of 0.8 microns). The ALBAGLOS PCC® powder is aprecipitated calcium carbonate product having prismatic and cubic shapedcrystals.

“Calcium Hydroxide[5]” refers to the calcium hydroxide powder having amedian particle size of about 5 microns available OMYA, Inc. Thismaterial comprises rhomboid shaped crystals of calcium hydroxide.

“Calcium mix” refers to a 1:1 mixture by weight of Calcium Hydroxide[5]and Calcium Carbonate[12]. The calcium mix has an median particle sizeof about 15 microns (14.8 microns).

Except in the case of Calcium Hydroxide[5], the foregoing medianparticle sizes are not those advertised by the manufacturer but ratherreflect median particle sizes as determined using a Coulter ParticleSize Analyzer as described in Example 2. All values represent the medianparticle size on a volume basis.

Example 1

The effects of calcium source, vitamin D, and L-lysine on calciumretention and bone quality was investigated in the rat model accordingto the procedure described in Zafar et al., “NondigestibleOligosaccharides Increase Calcium Absorption and Suppress BoneResorption in Ovariectomized Rats,” J. Nutrition, 123:399-402, 2004, thedisclosure of which is hereby incorporated by reference.

One hundred forty-four 3-week old Sprague-Dawley rats were randomizedinto nine groups (Groups 1-9) as listed in Table 1, with sixteen rats ineach group, and twenty five rats were randomized into six groups (Groups10-15) as listed in Table 2. For one week all rats (Groups 1-15) werefed a vitamin D-free AIN93-G control diet. At the end of week one (4weeks of age) the 144 rats (Groups 1-9) were switched to the study dietsadapted from the AIN93-G diet but containing the calcium, vitamin D,and/or L-lysine quantities listed in Table 1 and the 25 rats wereswitched to AIN96-G diets including the calcium, vitamin D, and/orL-lysine quantities listed in Table 2. At this time five rats from Group10 were sacrificed and serum was aliquoted for vitamin D assay.

TABLE 1 Particle Size Study Diets Rats Median Calcium Vitamin D L-LysineDiet Group (N) Calcium Source (μm) (mg) (I.U.) (mg) 1 1 16 CalciumCarbonate[12] 12 600 — — 2 2 16 Calcium Carbonate[12] 12 600 400 — 3 316 Calcium Carbonate[12] 12 600 400 100 4 4 16 Calcium Carbonate[12] 12600 400 200 5 5 16 Calcium Carbonate[16] 16 600 400 — 6 6 16 CalciumCarbonate[5] 5 600 400 — 7 7 16 Calcium Carbonate[2] 2 600 400 — 8 8 16Calcium Hydroxide[5] 5 600 400 — 9 9 16 Calcium Mix 15 600 400 —

TABLE 2 Vitamin D Status Study Diets Rats Median Calcium Vitamin DL-Lysine Diet Group (N) Calcium Source (μm) (mg) (I.U.) (mg) 1 10 15Calcium Carbonate[12] 12 600 — — 2 11 2 Calcium Carbonate[12] 12 600 400— 4 12 2 Calcium Carbonate[12] 12 600 400 200 6 13 2 CalciumCarbonate[5] 5 600 400 — 8 14 2 Calcium Hydroxide[5] 5 600 400 — 9 15 2Calcium Mix 15 600 400 —

During the first week of feeding all rats were placed in metabolic cagesfor two days to determine calcium balance according to the procedure setforth in Zafar et al., J. Nutrition, 123:399-402, 2004. Six rats fromeach groups received ⁴⁵Ca IP injections. At the end of the balancestudy, 10 rats from the Vitamin D study were sacrificed: 5 rats fromGroup 10 and 1 rat from each of Groups 11-15. After eight weeks on thetest diets, a two-day balance study was again conducted on ten rats fromeach groups according to the same procedure. At the end of the balancestudy, 10 rats from the Vitamin D status study were sacrificed: 5 ratsfrom Group 10 and 1 rat from each of Groups 11-15.

During week 10, all rats were sacrificed and both femurs and tibias wereharvested. One femur and tibia from each rat were used for weight andlength, bone breaking and calcium determination. Blood was collectedfrom a randomly selected subset of rats for Vitamin D status as follows:5 rats from Group 1 and one rat from each of Groups 2, 4, 6, 8 and 9.

Calcium analysis of diet, bones, feces, urine was determined by atomicabsorption spectrophotmetry (AAnalyst 300, Perkin Elmer, Shelton,Conn.). Percent calcium absorption was measures as(intake−feces)/intake*100. Bone Strength was determined by a three pointbending test (TA-XT2i, Texture Technologies, Corp, Scarsdale N.Y.), bonegeometry was determined by μCI′ 40 (Scanco Medical, Bassersdorf,Switzerland), and bone density was determined by underwater weighing,DXA (Lunar, Madison Wis.). Serum 25 OH D levels were measure by Gamma-B25-Hydroxy Vitamin D RIA (IDS, Inc).

Results: Calcium Balance

Calcium Balance data are provided in Tables 3 and 4. The data in Table 3shows the effect of each diet on two day calcium balance in four weekold rats after two days on the prescribed diet. The data in Table 4shows the effect of each diet on two day calcium balance in twelve-weekold rats after eight weeks on the prescribed diet. The values representthe group mean for all rats on the indicated diet (±SEM). The differentsuperscripts within the columns of Tables 3 and 4 representstatistically significant differences at a 95% confidence level(p<0.05).

TABLE 3 Ca Intake/2d Ca Absorption Ca Balance Diet (mg) (%) (mg/2d) 1107.6^(abcd) 86.6^(b) 92.9^(bc) (5.4) (1.6) (5.6) 2 129.3^(a) 92.1^(ab)118.9^(a) (9.7) (1.4) (9.8) 3 94.1^(cde) 85.7^(b) 86.4^(bc) (10.3) (5.7)(10.1) 4 102.4^(cde) 96.1^(a) 93.1^(bc) (10.3) (4.1) (10.1) 5 85.5^(e)94.3^(a) 78.9^(c) (8.5) (1.2) (8.4) 6 126.9^(a) 92.7^(ab) 117.5^(a)(8.9) (1.3) (9.1) 7 87.8^(de) 90.2^(ab) 78.5^(c) (5.3) (1.9) (5.5) 8115.0^(abc) 91.1^(ab) 102.9^(ab) (5.3) (1.3) (4.9) 9 118.4^(ab)92.9^(ab) 108.1^(ab) (3.8) (1.3) (3.7)

The calcium absorption efficiency data and calcium balance data of Table3 are plotted in FIGS. 3 and 4, respectively. It is notable that afteronly two days on the diet, rats fed Calcium Carbonate[12] plus 400 IU ofVitamin D (Diet 2) showed a significantly higher calcium balance thanrats fed Vitamin D deficient diets of Calcium Carbonate[12] (Diet 1).This finding is in accordance with other studies which have demonstratedthe importance of vitamin D in calcium absorption. The effect ofL-lysine on calcium balance appears to be negative, as both Diet 3 (100mg L-lysine) and Diet 4 (200 mg L-lysine) produced significantly lowercalcium balance than Diet 2 after two days. However, significance wasobserved with the 200 mg L-lysine diet as compared to the 100 mgL-lysine diet on the basis of absorption efficiency although thisdifference had no impact on calcium balance. The Vitamin D fortifieddiet of Calcium Carbonate[12] (Diet 2) also produced a statisticallysignificant improvement in calcium balance over the Vitamin D sufficientdiets of Calcium Carbonate[16] (Diet 5) and Calcium Carbonate[2] (Diet7).

Comparable data after eight weeks on the specified diets is provided inTable 4. The eight week data is considered to be more meaningful as itis likely to account for any adaptive effects of chronic feeding. Forexample, after eight weeks no significance is seen between the twoL-lysine diets for either calcium absorption efficiency or calciumbalance. In fact, L-lysine shows a statistically significant (p<0.05)negative effect on both percentage calcium absorption and calciumbalance as compared to Diet 2 when fed at a level of 200 mg (Diet 4).

TABLE 4 Ca Intake/2 d Ca Absorption Ca Balance Diet (mg) (%) (mg/2 d) 1117.5^(cd) 27.9^(d) 32.8^(c) (4.7) (3.6) (5.4) 2 139.3^(ab) 51.4^(a)69.9^(a) (5.1) (2.9) (5.3) 3 125.7^(cd) 47.9^(ab) 60.8^(ab) (5.5) (4.1)(7.2) 4 123.3^(bcd) 40.4^(bc) 47.6^(bc) (6.6) (3.3) (4.5) 5 113.6^(d)36.1^(cd) 39.0^(c) (4.6) (2.5) (3.8) 6 113.7^(d) 37.8^(bcd) 43.8^(bc)(5.7) (5.3) (7.1) 7 110.8^(d) 39.3^(bc) 41.8^(bc) (3.8) (2.5) (3.3) 8132.2^(abc) 44.3^(abc) 56.9^(ab) (4.3) (3.8) (5.6) 9 147.1^(a)44.0^(abc) 66.2^(a) (9.9) (4.7) (9.7)

The eight-week data in Table 4 also confirms the role of Vitamin D inimproving calcium absorption as the amount absorbed on a percentagebasis increased significantly (p<0.05) from 27.9% in the Vitamin Ddeficient diet (Diet 1) to 51.4% in the comparable Vitamin D sufficientdiet (Diet 2). Similarly, the calcium balance increased significantly(p<0.05) from 32.8% in the Vitamin D deficient diet (Diet 1) to 69.9% inthe sufficient Vitamin D diet (Diet 2).

Most notably, rats fed Calcium Carbonate[12] plus 400 IU of Vitamin D(Diet 2) showed the highest percentage absorption of calcium and calciumbalance after eight weeks. A significantly (p<0.05) higher percentagecalcium absorption and calcium balance was achieved with Diet 2 thanwith any other form of calcium carbonate, i.e., Diets 5, 6, and 7. Ratsfed Diet 2 had a 42.4% advantage in calcium absorption efficiency ascompared to rats fed Diet 5 (p<0.05). The effect of each diet on calciumabsorption after eight weeks on the diet is shown in FIG. 5. The effectof diet on calcium balance after eight weeks on the prescribed diets,shown in FIG. 6, parallel the effects of diet on absorption.

FIG. 7 compares calcium retention between rats fed Diet 2 versus ratsfed Diet 5, which notably is representative of the national leadingbrand, after two weeks on the diet (weanling rats) and eight weeks onthe diet (young adults). In weanling rats, the differences aresignificant at p=0.004. In young adult rats, the differences aresignificant at p<0.001. This data may be projected to humans to estimatethat an adolescent female will retain sufficiently more calcium toincrease bone mass by at least 4% over a one year period and potentiallymore than 8% over a two year period, relative to other forms of calciumcarbonate, by consuming Calcium Carbonate[12] plus 400 IU of Vitamin D

Results: Bone-Breaking

Table 5 provides the means values (±SEM) for the right femur dimensions,weight, and bone breaking peak force after eight weeks on the dietsshown in Tables 1 and 2.

TABLE 5 Length Width Dry Weight Underwater Peak Force Group (mm) (mm)(g) Weight (g) (g) Gradient 1 33.53 (0.29) 3.01 (0.13) 0.80 (0.02) 0.24(0.01)   9429^(a) (623) 11702 (1686) 2 33.85 (0.21) 3.11 (0.02) 0.88(0.01) 0.26 (0.00)  10993^(b) (247) 10462 (1825) 3 33.67 (0.16) 3.06(0.03) 0.82 (0.01) 0.26 (0.00) 10776^(ab) (206) 14754 (1414) 4 33.72(0.29) 3.06 (0.03) 0.85 (0.02) 0.26 (0.01) 10207^(ab) (266) 12818 (1469)5 33.65 (0.22) 3.07 (0.03) 0.85 (0.02) 0.26 (0.01) 10218^(ab) (278)13480 (1822) 6 33.80 (0.20) 3.06 (0.02) 0.85 (0.02) 0.26 (0.01)10398^(ab) (265) 12707 (1864) 7 33.61 (0.20) 3.06 (0.03) 0.85 (0.02)0.26 (0.00) 10697^(ab) (264) 13252 (1707) 8 33.72 (0.24) 3.07 (0.04)0.90 (0.02) 0.26 (0.00) 10320^(ab) (205) 12745 (1567) 9 33.70 (0.17)3.04 (0.03) 0.84 (0.02) 0.26 (0.01)  10888^(b) (799) 12657 (1631)

The different superscripts within the peak break force column representstatistically significant differences at a 95% confidence level(p<0.05). There were significant differences in peak bone breaking forceof the femur (p=0.0251): peak breaking force of femurs of rats on Diet 1(vitamin D deficient) was significantly lower than for rats on Diet 2(the same calcium source plus Vitamin D) or for rats on Diet 9. At a 90%confidence interval (p<0.10) the differences in peak bone breaking forceof the femur between rats on Diets 2 and 5 were significant. Thesignificance between Diets 2 and 5 was p=0.04 using a one-tailed T-test.Thus, it may be concluded that Calcium Carbonate[12] provides astatistically significant increase in peak bone breaking force ascompared to rats fed Calcium Carbonate[16]. The peak breaking force dataof Table 5 is plotted in FIG. 8.

Results: Calcium Content of Bone

The levels of calcium in the tibia were analyzed for the rats on Diets1, 2 and 5 after eight weeks on the prescribed diets by atomicabsorption spectroscopy after dissolving the tibias in acid. The groupmeans and standard errors of measurement for tibial calcium content areshown in Table 6.

TABLE 6 Diet Ca (mg)/tibia 1 85 (SEM ± 2.0) 2 91 (SEM ± 1.3) 5 88 (SEM ±1.8)

The rats on Diet 2 exhibited higher levels of calcium in the tibia aftereight weeks feeding than either the vitamin D deficient diet (Diet 1) orthe Calcium Carbonate[16] diet (Diet 5), which was selected tocorrespond to the national leading brand of calcium supplement. BetweenDiets 1 and 2 the differences were significant at p=0.004 and betweenDiets 2 and 5 the differences were significant at p=0.056 using aone-tailed T-test.

In summary, rats fed Calcium Carbonate[12] (Diet 2) exhibited superiorpercent calcium absorption, calcium balance, bone dimension (length andwidth), bone weight, peak break force, and gradient (i.e., boneflexibility) than rats fed any other form of calcium carbonate aftereight weeks on calcium fortified diets. Also, tibial calcium content wassignificantly greater in rats fed Calcium Carbonate[12] (Diet 2) thanrats fed Calcium Carbonate[16] (Diet 5), chosen to correspond to thecalcium carbonate of the national leading brand.

Determination of Intraperitoneal Ionized Calcium

To further investigate the improved bioavailability of the calciumcarbonate according to the invention, the calcium ion concentration[Ca⁴²] in the peritoneal interstitial fluid (ISF) of rats was determinedusing an ultrafiltrate probe. The ultrafiltrate probe is a device whichcan sample ISF in vivo in an awake, freely moving animal. Theultrafiltrate probe comprises semi-permeable hollow fiber membranes witha 30,000 molecular weight cut-off attached to a non-permeable tube. Thefibers are implanted in the tissue to be sampled, in this case, theperitoneal cavity, and the microbore tubing is externalized. A negativepressure is applied to the tubing and the ISF flows into the tubing downthe pressure gradient. Samples are collected externally at desiredintervals. The ultrafiltrate probe has previously been described andemployed to study tissue glucose in diabetes (Janle-Swain et al.,American Society of Artificial Internal Organs Transactions, 33:336-340,1987; Janie et al., Current Separations, 14:58-63, 1995; and Janie etal., Journal of Herbal Pharmacotherapy, 5:55-64, 2005), electrolytes andmetabolites in simulated weightlessness (Janie et al., Acta Astonautica,43:87-99, 1998), and distribution of dietary calcium (Janie et al.,Contemporary Topics in Laboratory Animal Science, 39:46-50, 2000; andSoji et al., Journal of Investigative Surgery, 13:289-249, 2000), eachof which is hereby incorporated by reference herein.

In this study, six female Harlan Sprague Dawley rats (200-225 g, 65-75days old) were randomly assigned to two groups. Each groups received anutritionally complete diet based on AIN-93G formulation and containing0.5% calcium. For the rats in group 1, the calcium was provided by theCalcium Carbonate[12] powder and for the rats in group 2 the calcium wasprovided by the Calcium Carbonate[16] powder. The rats were meal trainedfor a week to eat food when presented to them.

Ultrafiltrate probes were implanted into the peritoneal cavities of therats and ISF samples were collected at regular intervals for two days.The ultrafiltrate samples were analyzed for ionized calcium using aclinical analyzer. The results of the analysis for ionized calciumconcentration in the peritoneal ISF for the group 1 rats receiving theCalcium Carbonate[12] compared to the group 2 rats receiving the CalciumCarbonate[16] diets are shown in FIG. 27. In FIG. 27, “Day 1 ON”designates the first day of the study and corresponds to a measurementcycle during which the rats had access to the food, “K1 Fast”corresponds to a period following “Day 1 ON” during which food had beenremoved from the rats for about four hours, and “K1 Test” corresponds toa measurement during a subsequent feeding cycle on day one of the study.

As shown in FIG. 27, during the initial measurement, “Day 1 ON,” theCalcium Carbonate[16] diet (group 2) provided a slightly higher calciumion concentration in the ISF as compared to the Calcium Carbonate[12]diet (group 1), although the differences were not statisticallysignificant. However, during the subsequent fasting cycle “K1 Fast” therats fed Calcium Carbonate[12] exhibited a substantially higher calciumion concentration in the ISF as compared to the rats fed CalciumCarbonate[16]. This result was also observed during the subsequentfeeding period “K1 Test.”

It is believed that during the initial feeding on day one (“Day 1 ON”),both diets yielded substantially the same calcium ion concentration inthe peritoneal ISF because during continuous feeding there isessentially a continuous infusion of calcium carbonate to maintain theactive transport mechanism in a saturated state, as well as a continuoussupply of particles of appropriate size to optimize passive transport.However, during the fasting cycle (“K1 Fast”), the Calcium Carbonate[12]powder clearly produced a higher [Ca⁺²] in the ISF which is believed tohave resulted from the fact that this powder provides more material inthe intermediate particle size range as compared to the CalciumCarbonate[16] powder, and is thus capable of metering out a moresubstantial volume of particles capable of active transport and passivediffusion across the intestine over a longer time course. Surprisingly,even during the subsequent feeding cycle “K1 Test,” the superiority ofCalcium Carbonate[12] continues to manifest and is evidently notoutweighed by the effects of continuous feeding.

The ultrafiltrate samples were collected for a second day under the samefeeding conditions as day one. As shown in FIG. 27, the peritonealcalcium ion concentration was dramatically higher for rats fed theCalcium Carbonate[12] powder as compared to rats fed the CalciumCarbonate[16] powder during the first feeding cycle on day 2, designatedas “Day 2 ON,” and was also substantially higher during the subsequentfasting cycle “K2 Fast,” similar to what was observed on day one. Thenext measurement on day 2, showed a very slight 0.05 mM) difference incalcium ion levels between the two diets, with the group 2 ratsexhibiting negligibly higher levels of calcium ion in the ultrafiltrate.However, this result was discarded as spurious, as it was determinedthat the ultrafiltrate probes had become dislodged in several rats.

Example 2

The particle size distributions of commercially available calciumcarbonate powders were determined. Samples A, B, and C were each samplesof Calcium Carbonate[12]. Samples D, E, and F were each samples ofCalcium Carbonate[16]. Sample G was Calcium Carbonate[5] and Sample Hwas Calcium Carbonate[2].

The particle size distributions were obtained using a Beckman CoulterLS13 320 Particle Size Analyzer with the Aqueous Liquid Sample Module.Each calcium carbonate sample was dispersed in water and added to theAqueous Liquid Sample Module using transfer pipettes. The particle sizedistributions were calculated by using an optical model for calciumcarbonate with the following parameters: Diluent R.I=1.333; Sample RealR.I.=1.596; Imaginary=0.1. The distributions were measured over therange of channel diameters from 0.04 microns to 2,000 microns.

The distributions of Samples A, B, and C (Calcium Carbonate[12]) areplotted in FIG. 9 as the differential volume percent between eachchannel diameter and in FIG. 10 as the cumulative volume percent ofparticle size less than the channel diameter. The particle sizedistributions of Samples A, B, and C were then averaged by taking thearithmetic mean at each channel diameter. The resulting averagedistribution of Samples A, B, and C, referred to herein as X _((A,B,C)),is shown in FIG. 11 as the differential volume percent between eachchannel diameter and in FIG. 12 as the cumulative volume percent ofparticle size less than the channel diameter. FIGS. 13-16 shows X_((A,B,C)) as cumulative volume percent less than the channel diameteracross the indicated size range (bold line) along with the distributioncurves corresponding to ±1 SD (standard deviation from the mean at eachdiameter), ±2 SD, and ±3 SD (thin lines), wherein the pair of curvescorresponding to ±3 SD are the outermost, the pair of curvescorresponding to ±1 SD are the inner-most to the bold X _((A,B,C))curve, and the pair of curves corresponding to ±2 SD are intermediatethe ±1 SD and ±3 SD curves. Table 7 provides the numerical datacorresponding to FIG. 13-16.

TABLE 7 CUMULATIVE VOLUME (%) OF PARTICLES OF SIZE LESS THAN CHANNELDIAMETER Channel Diameter X _((A,B,C)) X _((A,B,C)) X _((A,B,C)) X_((A,B,C)) X _((A,B,C)) X _((A,B,C)) (microns) _((−3SD)) _((−2SD))_((−1SD)) X _((A,B,C)) _((+1SD)) _((+2SD)) _((+3SD)) 0.040 0.0000 0.00000.0000 0.0000 0.0000 0.0000 0.0000 0.044 0.0017 0.0017 0.0018 0.00190.0020 0.0021 0.0022 0.048 0.0037 0.0040 0.0042 0.0044 0.0047 0.00490.0051 0.053 0.0070 0.0074 0.0079 0.0083 0.0088 0.0092 0.0097 0.0580.0135 0.0144 0.0154 0.0163 0.0173 0.0182 0.0192 0.064 0.0278 0.02920.0306 0.0320 0.0334 0.0348 0.0362 0.070 0.0528 0.0561 0.0594 0.06270.0660 0.0693 0.0726 0.077 0.0925 0.0972 0.1020 0.1067 0.1114 0.11610.1208 0.084 0.1450 0.1545 0.1639 0.1733 0.1828 0.1922 0.2016 0.0930.2076 0.2217 0.2359 0.2500 0.2641 0.2783 0.2924 0.102 0.2923 0.30930.3263 0.3433 0.3603 0.3773 0.3943 0.112 0.3852 0.4068 0.4284 0.45000.4716 0.4932 0.5148 0.122 0.4979 0.5242 0.5504 0.5767 0.6029 0.62920.6554 0.134 0.6177 0.6507 0.6837 0.7167 0.7497 0.7827 0.8157 0.1480.7558 0.7961 0.8364 0.8767 0.9169 0.9572 0.9975 0.162 0.9084 0.95340.9984 1.0433 1.0883 1.1333 1.1782 0.178 1.076 1.128 1.181 1.233 1.2861.338 1.391 0.195 1.251 1.313 1.375 1.437 1.498 1.560 1.622 0.214 1.4511.520 1.588 1.657 1.725 1.794 1.862 0.235 1.669 1.745 1.821 1.897 1.9732.048 2.124 0.258 1.912 1.992 2.073 2.153 2.234 2.314 2.395 0.284 2.1672.257 2.347 2.437 2.527 2.617 2.706 0.311 2.449 2.544 2.639 2.733 2.8282.923 3.017 0.342 2.762 2.861 2.961 3.060 3.159 3.259 3.358 0.375 3.0773.186 3.295 3.403 3.512 3.621 3.730 0.412 3.434 3.545 3.656 3.767 3.8783.988 4.099 0.452 3.802 3.920 4.039 4.157 4.275 4.393 4.511 0.496 4.2124.330 4.449 4.567 4.685 4.803 4.921 0.545 4.649 4.769 4.890 5.010 5.1305.251 5.371 0.598 5.109 5.229 5.350 5.470 5.590 5.711 5.831 0.656 5.5965.718 5.841 5.963 6.086 6.208 6.331 0.721 6.116 6.238 6.361 6.483 6.6066.728 6.851 0.791 6.687 6.802 6.918 7.033 7.149 7.264 7.380 0.868 7.2627.380 7.499 7.617 7.735 7.853 7.971 0.953 7.907 8.016 8.125 8.233 8.3428.451 8.560 1.047 8.560 8.666 8.773 8.880 8.987 9.094 9.200 1.149 9.2599.359 9.460 9.560 9.660 9.761 9.861 1.261 9.893 10.02 10.14 10.27 10.3910.52 10.64 1.384 10.75 10.84 10.94 11.03 11.13 11.22 11.32 1.520 11.5511.64 11.74 11.83 11.93 12.02 12.12 1.668 12.35 12.44 12.54 12.63 12.7312.82 12.92 1.832 13.08 13.22 13.36 13.50 13.64 13.78 13.92 2.011 13.9814.12 14.26 14.40 14.54 14.68 14.82 2.207 14.82 14.99 15.16 15.33 15.5015.67 15.84 2.423 15.65 15.87 16.08 16.30 16.52 16.73 16.95 2.660 16.5816.84 17.10 17.37 17.63 17.89 18.15 2.920 17.61 17.92 18.22 18.53 18.8419.15 19.46 3.205 18.58 18.96 19.35 19.73 20.12 20.51 20.89 3.519 19.5720.07 20.57 21.07 21.57 22.06 22.56 3.863 20.73 21.31 21.89 22.47 23.0523.63 24.20 4.240 22.00 22.66 23.33 24.00 24.67 25.34 26.00 4.655 23.4424.18 24.93 25.67 26.41 27.15 27.89 5.110 24.84 25.70 26.57 27.43 28.3029.16 30.03 5.610 26.43 27.42 28.41 29.40 30.39 31.38 32.37 6.158 28.1229.24 30.35 31.47 32.58 33.70 34.81 6.760 30.00 31.23 32.47 33.70 34.9336.17 37.40 7.421 31.99 33.35 34.71 36.07 37.42 38.78 40.14 8.147 34.1735.65 37.12 38.60 40.08 41.55 43.03 8.943 36.40 38.05 39.69 41.33 42.9844.62 46.26 9.818 39.06 40.78 42.51 44.23 45.96 47.68 49.41 10.78 41.6743.56 45.45 47.33 49.22 51.11 53.00 11.83 44.75 46.72 48.69 50.67 52.6454.61 56.59 12.99 48.10 50.16 52.21 54.27 56.32 58.38 60.43 14.26 51.6653.79 55.93 58.07 60.20 62.34 64.47 15.65 55.43 57.65 59.88 62.10 64.3266.55 68.77 17.18 59.63 61.85 64.08 66.30 68.52 70.75 72.97 18.86 63.9566.18 68.40 70.63 72.86 75.09 77.32 20.71 68.59 70.74 72.88 75.03 77.1879.33 81.48 22.73 73.55 75.50 77.45 79.40 81.35 83.30 85.25 24.95 78.4080.17 81.93 83.70 85.47 87.23 89.00 27.39 83.45 84.90 86.35 87.80 89.2590.70 92.15 30.07 87.90 89.09 90.28 91.47 92.66 93.85 95.04 33.01 91.8792.77 93.67 94.57 95.47 96.37 97.26 36.24 95.16 95.75 96.34 96.93 97.5298.11 98.71 39.78 97.43 97.79 98.14 98.50 98.86 99.21 99.57 43.67 98.9299.09 99.26 99.43 99.60 99.77 99.94 47.94 99.73 99.77 99.82 99.87 99.9199.96 100.0 52.62 99.92 99.94 99.96 99.97 99.99 100.0 100.0 57.77 99.9999.99 100.0 100.0 100.0 100.0 100.0 63.41 100.0 100.0 100.0 100.0 100.0100.0 100.0

As used herein, the phrase “similar to,” when used in reference to theparticle size distribution of X _((A,B,C)) expressed as cumulativevolume percent of particles of size less than the channel diameter (asshown in FIGS. 13-16), means within ±3SD of the corresponding cumulativevolume percent for X _((A,B,C)) at each channel diameter. Similarly, theterm “approximately the same as,” when used in reference to the particlesize distribution of X _((A,B,C)) expressed as cumulative volume percentof particles of size less than the channel diameter (as shown in FIGS.13-16), means within ±SD of the corresponding cumulative volume percentfor X _((A,B,C)) at each channel diameter. The term “substantiallyidentical to,” when used in reference to the particle size distributionof X _((A,B,C)) expressed as cumulative volume percent of particles ofsize less than the channel diameter (as shown in FIGS. 13-16), meanswithin ±1SD of the corresponding cumulative volume percent for X_((A,B,C)) at each channel diameter. The data in Table 7 is provided toassist the skilled artisan in determining if a distribution is “similarto,” “approximately the same as,” or “substantially identical to” theparticle size distribution of X _((A,B,C)).

The distributions of Samples D, E, and F (Calcium Carbonate[16]) areplotted in FIG. 17 as the differential volume percent between eachchannel diameter and in FIG. 18 as the cumulative volume percent ofparticle size less than the channel diameter. The particle sizedistributions of Samples D, E, and F were likewise averaged by takingthe arithmetic mean at each channel diameter. The resulting averagedistribution X _((D,E,F)) is shown in FIG. 19 as the differential volumepercent between each channel diameter and in FIG. 20 as the cumulativevolume percent of particle size less than the channel diameter (boldline), along with the distribution curves corresponding to +1 SD(standard deviation from the mean at each diameter), +2 SD, and +3 SD(thin lines). FIG. 21 is an expansion of FIG. 20 to show theintermediate particle size region, in this case, from 1 to 10 microns.

FIGS. 22 and 23 compare the distributions of X _((A,B,C)) and X_((D,E,F)) as differential volume percent between each channel diameteracross and as the cumulative volume percent of particle size less thanthe channel diameter, respectively. FIG. 24 compares the distributionsof X _((A,B,C)) (including −1 SD, −2 SD, and −3 SD) with the X_((D,E,F)) (including +1 SD, +2 SD, and +3 SD) distribution asdifferential volume percent between each channel diameter across therange of 1 to 10 microns. It can be seen that substantial differencebetween these powders are evident even at ±3SD, as the curvecorresponding to X _((A,B,C))−3SD is substantially above that of X_((A,B,C))+3SD across substantially all of the intermediate size rangefrom 1 to 10 microns.

FIG. 25 shows the distributions of X _((A,B,C)), X _((D,E,F)), Sample G,and Sample H expressed as cumulative volume percent of particle sizebetween the channel diameters. Inspection of FIG. 25 reveals that X_((A,B,C)) is the only powder which provides substantial volume underthe curve at both the intermediate and large particle size ranges. Whilethe distribution of Sample H is robust in the small particle range, itis deficient in both intermediate and large particles. Sample G providesthe substantial portion of its volume in the intermediate size range,but likewise has very little area under the curve in the large particleregion. The deficiency of these powders in the rat studies of Example 1,relative to Calcium Carbonate[12], can be explained on this basis.Similarly, X _((D,E,F)) is also inferior to X _((A,B,C)) in theintermediate particle size region, though it does provide more volume inthe large particle size region. The results detailed in Example 1therefore compel the conclusion that optimal in vivo utilization ofcalcium requires more volume in the intermediate particle size rangethan is provided by X _((D,E,F)).

The distributions may be defined by various well known descriptivestatistical parameters including mean (arithmetic mean by volume),median (i.e., the particle size at which half the volume is above andhalf the volume is below), mode (most common particle size by volume),mean to median ratio (mean/median), standard deviation (SD), variance,coefficient of variance (CV), skewedness, and kurtosis (leptokurtic orplatykurtic). The distributions can also be characterized by the D₁₀,D₅₀, and D₉₀ values which represent the particle diameters at which 10%,50% and 90% of the sample volume, respectively, is less than thatdiameter. The surface area of the various powders may be defined interms of specific surface area (SSA) or the surface area mean momentD[3,2]. The specific surface area is defined as the ratio of the surfacearea to mass and provided in units of cm²/g. The surface area meanmoment D[3,2] is the diameter of a particle having the samevolume/surface area ratio as the entire distribution and defined by theequation:

${D\left\lbrack {3,2} \right\rbrack} = \frac{\sum\limits_{i}d_{i}^{3}}{\sum\limits_{i}d_{i}^{2}}$

Table 8 provides the descriptive statistics for the particle sizedistributions for calcium carbonate powders according to the invention,i.e., samples A, B, C, and X _((A,B,C)), in comparison with calciumcarbonate powders of lesser bioavailability, i.e., samples D, E, F, G, Hand X _((D,E,F)).

TABLE 8 A B C X _((A.B,C)) D E F X _((D,E,F)) G H mean (μm) 13.39 12.9914.31 13.56 18.55 16.15 17.04 17.25 5.08 14.78 median (μm) 11.52 10.9412.46 11.64 17.04 15.11 16.24 16.13 4.59 1.99 D[3,2] (μm) 2.41 2.39 2.532.44 2.86 2.66 2.77 2.76 — 0.88 mean/median 1.62 1.187 1.15 1.32 1.0891.069 1.05 1.069 1.105 7.4 mode (μm) 21.69 18.00 23.81 21.17 26.14 21.6923.81 23.88 6.45 1.32 SSA (cm²/g) 9180 9268 8753 9067 7748 8330 79828020 — 25037 SD (μm) 10.41 10.3 11.05 10.59 13.56 10.97 11.18 11.903.603 34.04 variance (μm²) 108.3 106.2 122.1 112.2 183.8 120.3 125 143.012.98 1158 CV (%) 77.7 79.3 77.2 78.1 73.1 67.9 65.6 68.9 70.9 230skewedness 0.70 0.80 0.67 0.72 1.12 0.48 0.39 0.66 0.68 3.30 kurtosis−0.25 0.01 −0.28 −0.17 3.34 −0.38 −0.48 0.83 −0.04 10.66 D₁₀ (μm) 1.2031.21 1.24 1.22 1.66 1.47 1.64 1.59 0.62 0.33 D₅₀ (μm) 11.52 10.94 12.4611.64 17.04 15.11 16.24 16.13 4.59 1.99 D₉₀ (μm) 28.55 28.01 30.20 28.9235.88 31.51 32.48 33.29 10.19 41.86

The calcium carbonate powders according to the invention, represented inTable 8 as samples A, B, C, and X _((A,B,C)) may be described in term ofany one of the parameters of Table 8, or any combinations thereof. Insome embodiments, the calcium carbonate powders according to theinvention are described in terms of their D₁₀, D₅₀, and D₉₀ values.Table 9 shows the D₁₀, D₅₀, and D₉₀ values for X _((A,B,C)) as well asthe values corresponding to ±1 SD, ±2SD, and ±3SD of the mean, each ofwhich is considered to be an embodiment of the invention.

TABLE 9 D₁₀ D₅₀ D₉₀ X _((A,B,C)) + 3SD 1.27 13.5 31.7 X _((A,B,C)) + 2SD1.25 12.9 30.8 X _((A,B,C)) + 1SD 1.24 12.3 29.9 X _((A,B,C)) 1.22 11.628.9 X _((A,B,C)) − 1SD 1.20 11.0 28.0 X _((A,B,C)) − 2SD 1.19 10.4 27.1X _((A,B,C)) − 3SD 1.17 9.8 26.1

Accordingly, the invention embraces embodiments having a D₁₀ valueranging from about 1.17 to about 1.27 microns, about 1.19 to about 1.25micron, about 1.20 to about 1.24 microns, or about 1.22 microns.Similarly, various embodiments will have a D₅₀ value ranging from about9.8 to about 13.5 microns, about 10.4 to about 12.9 microns, about 11 toabout 12.3 microns, and about 11.6 microns. The D₉₀ value in variousembodiments will range from about 26.1 to about 31.7 microns, about 27.1to about 30.8 microns, about 28.0 to about 29.9 microns. Anycombinations of these ranges and sub-ranges are also considered to bewithin the scope of the invention but are omitted herein for brevity. Inone embodiment, the D90 value will be about 28.9 microns.

As discussed above, the exceptional bioavailability of the calcium formsof the invention is believed to result, in part, from the volume ofparticles in the intermediate size range. The particle size data acrossan exemplary intermediate particle size range for X _((A,B,C)) and X_((D,E,F)) (including ±1SD, ±2SD, and ±3SD of the mean at each particlesize) is provided in Table 10 along with the corresponding data forSamples G and H.

TABLE 10 Cumulative Volume (%) of Particles of Size Less than ChannelDiameter Channel Diameter X _((A,B,C)) X _((A,B,C)) X _((A,B,C)) X_((D,E,F)) X _((D,E,F)) X _((D,E,F)) Sample Sample (microns) X_((A,B,C)) (−1SD) (−2SD) (−3SD) X _((D,E,F)) (+1SD) (+2SD) (+3DS) G H1.05 8.9 8.8 8.7 8.6 7.8 8.1 8.3 8.6 14.8 32.2 1.15 9.6 9.5 9.4 9.3 8.38.6 8.8 9.1 15.8 34.8 1.26 10.3 10.1 10.0 9.9 8.8 9.1 9.3 9.6 16.9 37.51.38 11.0 10.9 10.8 10.8 9.3 9.6 9.9 10.1 18.1 40.2 1.52 11.8 11.7 11.611.6 9.8 10.1 10.4 10.7 19.3 42.9 1.69 12.6 12.5 12.4 12.4 10.3 10.610.9 11.2 20.7 45.5 1.83 13.5 13.4 13.2 13.1 10.7 11.1 11.4 11.7 22.248.0 2.01 14.4 14.3 14.1 14.0 11.2 11.6 11.9 12.2 23.8 50.2 2.21 15.315.2 15.0 14.8 11.7 12.1 12.4 12.8 25.6 52.1 2.42 16.3 16.1 15.9 15.712.2 12.6 12.9 13.3 27.6 53.7 2.66 17.4 17.1 16.8 16.6 12.7 13.1 13.413.8 29.8 55.1 2.92 18.5 18.2 17.9 17.6 13.2 13.6 13.9 14.3 32.4 56.33.21 19.7 19.3 19.0 18.6 13.8 14.2 14.6 15.0 35.3 57.4 3.52 21.1 20.620.1 19.6 14.4 14.9 15.3 15.8 38.5 58.6 3.86 22.5 21.9 21.3 20.7 15.115.6 16.1 16.5 42.2 59.8 4.24 24.0 23.3 22.7 22.0 15.8 16.4 16.9 17.446.2 61.2 4.66 25.7 24.9 24.2 23.4 16.7 17.3 17.8 18.3 50.6 62.8 5.1127.4 26.6 25.7 24.8 17.7 18.3 19.0 19.6 55.3 64.5 5.61 29.4 28.4 27.426.4 18.9 19.6 20.3 21.0 60.2 66.3 6.16 31.5 30.4 29.2 28.1 20.3 21.021.7 22.5 65.2 68.0 6.76 33.7 32.5 31.2 30.0 21.8 22.6 23.5 24.3 70.369.8 7.42 36.1 34.7 33.4 32.0 23.6 24.5 25.4 26.2 75.3 71.4 8.15 38.637.1 35.6 34.2 25.6 26.6 27.6 28.6 80.1 72.9 8.94 41.3 39.7 38.0 36.427.9 29.0 30.2 31.3 84.6 74.3 9.82 44.2 42.5 40.8 39.1 30.5 31.8 33.134.3 88.6 75.8 10.78 47.3 45.4 43.6 41.7 33.4 34.9 36.4 37.8 92.1 77.2

The intermediate particle size range may encompass the entire size rangeof Table 10 (i.e., 1.05 to 10.78 microns) or may consist of anysub-range therein (e.g., 1.05 to 8.94 microns or 1.26 microns to 9.82microns), each of which is omitted herein for brevity but will beunderstood to comprise distinct embodiments of the invention. Further,the intermediate particle size range may be defined at the lower end ofthe range by any of the values described elsewhere herein, includingabout 0.25 microns, about 0.5 microns, about 0.75 microns, or about 1micron and defined at the upper end by any of the particle size valuesin Table 7 or Table 10. Similarly, the lower end of the intermediateparticle size range may be defined by any of the values in Table 7 orTable 10 and the upper end of the range defined by any of the valuesdescribed elsewhere herein, including about 20 microns, about 15microns, about 12.5 microns, and about 10 microns.

The volume percent of calcium carbonate particles within theintermediate size range may be, without limitation, the volume percentof X _((A,B,C)) (−3SD) or greater at each particle size, the volumepercent of X _((A,B,C)) (−2SD) or greater at each particle size, thevolume percent of X _((A,B,C)) (−1SD) or greater at each particle size,the volume percent of X _((A,B,C)) or greater at each particle diameter,or the volume percent of calcium carbonate particles within theintermediate size range may be defined as greater than the volumepercent of at each particle diameter, greater than the volume percent ofX _((D,E,F)) (+1SD) at each particle diameter, greater than the volumepercent of X _((D,E,F)) (+2SD) at each particle diameter, or greaterthan the volume percent of X _((D,E,F)) (+3SD) at each particlediameter. The invention further embraces intermediate size range volumepercents defined on the lower end of the range as the volume percent ofany of X _((A,B,C)) (−3SD), X _((A,B,C)) (−2SD), X _((A,B,C)) (−1SD), X_((D,E,F)), X _((D,E,F)) (+1SD), X _((D,E,F)) (+2SD), or X _((D,E,F))(+3SD) where the upper end of the volume percent range for particles ofintermediate size is not critical and is only limited by the requirementthat sufficient volume be provided in the large particle size range and,optionally, in the small particle size range. In some embodiments, theupper end of the volume percent range may be the volume percent of anyof X _((A,B,C)) (+3SD), X _((A,B,C)) (+²SD), or X _((A,B,C)) (+1SD) overthe same particle size range, the data for which is provided in Table 7above.

Table 11 compares the volume (%) of particles of size less than 1.05microns between X _((A,B,C)) (including ±3SD), X _((D,E,F)), Sample G,and Sample H. It is apparent that Sample H has a substantially largervolume of particles in the small particle size range than any of theother powders, whereas X _((D,E,F)) has the least volume in this range.In embodiment where the small particle range is defined as less thanabout 1 micron, preferred calcium carbonate powders according to theinvention will have volume percents of greater than about 8 microns,greater than about 10 percent, greater than about 11 percent. Whilethere is essentially no constraint placed on the upper limit of thevolume in the small particle size range, it should not be so large as toreduce the volume of particles in the large particle size range or moreimportant intermediate size ranges. Thus, preferred calcium carbonatepowders will have at most about 15 percent and preferably at most about13 percent of the volume in the small particle size range, particularlywhere the small range is defined as particle less than 1 micron indiameter.

TABLE 11 Volume (%) of Particles of Size Less Than Channel Diameter of1.05 microns Sample H 32.2 Sample G 14.8 X _((A,B,C)) + 3SD 12.1 X_((A,B,C)) 11.8 X _((A,B,C)) − 3SD 11.6 X _((D,E,F)) 7.9

Table 12 compares the volume percent of particles in the intermediatesize range expressed as the difference between volume (%) of particlesof size less than 10.78 microns and volume (%) of particles of size lessthan 1.05 microns for X _((A,B,C)) (including −3SD, −2SD, and −1SD), X_((D,E,F)) (including +1SD, +2SD, and +3SD), Sample G, and Sample H. Thedata in Table 12 is obtained by subtracting the total volume percentless than 1.05 microns from the total volume percent less than 10.78microns and therefore may be said to represent the volume percent ofparticles in the intermediate range from and including 1.05 microns toless than 10.78 microns.

TABLE 12 Difference Between Volume (%) of Particles of Size Less ThanChannel Diameter of 10.78 microns and Volume (%) of Particles of SizeLess Than Channel Diameter of 1.05 microns Sample H 47.4 Sample G 77.3 X_((A,B,C)) + 3SD 43.8 X _((A,B,C)) + 2SD 42.0 X _((A,B,C)) + 1SD 40.4 X_((A,B,C)) 38.4 X _((A,B,C)) − 1SD 36.6 X _((A,B,C)) − 2SD 34.9 X_((A,B,C)) − 3SD 33.1 X _((D,E,F)) + 3SD 29.7 X _((D,E,F)) + 2SD 28.1 X_((D,E,F)) + 1SD 26.8 X _((D,E,F)) 25.6

As shown in Table 12, X _((D,E,F)) provides the least volume percent inthe intermediate size range of about 1 to about 11 microns. Thus, thevolume percent required to achieved enhanced absorption efficiency is,according to one embodiment, at least about 26 percent. With due regardfor the standard deviations of the X _((D,E,F)) powder, otherembodiments include without limitation, at least about 27 percent byvolume, at least about 28 percent by volume, and at least about 30percent by volume, particularly where the intermediate range is definedas about 1 micron to about 11 microns. In other embodiments, theintermediate range will comprise about 33 percent or more, about 35percent or more, or about 36 percent or more of the total volume ofcalcium carbonate powder, particularly where the intermediate range isdefined as about 1 to about 11 microns. The upper end of the volumerange is not particularly limited but must not be so large as tosubstantially reduce the volume of particles in the small size regionor, more significantly, in the large particle size region. For example,Sample G (Calcium Carbonate[5]) possess the most volume in theintermediate particle size range, having the substantial bulk of itsvolume within the range of about 1 to about 11 microns. However, asdemonstrated in Example 1, Calcium Carbonate[5] does not shownsignificant improvement in absorption efficiency or calcium balanceafter an eight-week feeding regimen as compared to any of the othercalcium carbonate powders. As shown in Table 13, Sample G is clearlydeficient in the large particle size region. Thus, in preferredembodiments, the calcium carbonate of the invention will have a volumepercent range of intermediate size particles defined at the upper end byabout 60, about 55, or about 50 percent of the total volume of calciumcarbonate, and more preferably about 40 percent, about 42 percent, andabout 44 percent of the total volume of calcium carbonate, particularlywhere the intermediate size range is defined as about 1 micron to about11 microns.

In one embodiment, the intermediate particle size range is about 1micron to about 11 microns and the volume percent of particles withinthis range is about 33 to about 44 percent, about 35 to about 42percent, about 36 to about 41 percent, about 37 to about 41 percent, orabout 38 percent. In another embodiment, the intermediate particle sizerange is about 0.5 microns to about 11 microns and the volume percent ofparticles within this range is about 37 to about 49 percent, about 40 toabout 46 percent, about 42 percent to about 44 percent, or about 43percent. Preferred volume percent ranges are established over any givenrange of intermediate particle sizes as the volume percent differencesbetween X _((A,B,C)) (+3SD) and X _((A,B,C)) (−3SD); X _((A,B,C)) (+2SD)and X _((A,B,C)) (−2SD); or X _((A,B,C)) (+1 SD) and X _((A,B,C)) (−1SD)over the particle size range which can be readily calculated based onthe data provided in Table 7.

Table 13 compares the volume percent of particles in the large particlesize region for the various calcium carbonate powders. It is seen thatSample G lacks substantial volume of large particles, such as particlesgreater than about 11 microns in diameter. This observation is believedto explain the inability of Calcium Carbonate[5] to increase calciumabsorption efficiency and calcium balance relative to other calciumcarbonate powders, as described in Example 1. Sample G (CalciumCarbonate[2]) is similarly deficient.

TABLE 13 Volume (%) of Particles of Size Greater Than Channel Diameterof 10.78 microns X _((D,E,F)) 66.6 X _((A,B,C)) + 3SD 58.3 X_((A,B,C)) + 2SD 56.4 X _((A,B,C)) + 1SD 54.6 X _((A,B,C)) 52.7 X_((A,B,C)) − 1SD 50.8 X _((A,B,C)) − 2SD 48.9 X _((A,B,C)) − 3SD 47.0Sample G 7.9 Sample H 22.8

In the broadest embodiments of the invention, the volume percent oflarge particles will typically be greater than 23 percent, and moretypically will be greater than about 30 percent, preferably greater thanabout 35 percent, and more preferably greater than about 40 percent ofthe total volume of the calcium carbonate powder. Preferred volumepercent ranges of large particles may be defined as, for example, thevolume percent ranges defined at the upper and lower ends by X_((A,B,C)) (+3SD) and X _((A,B,C)) (−3SD); X _((A,B,C)) (+2SD) and X_((A,B,C)) (−2SD); or X _((A,B,C)) (+1SD) and X _((A,B,C)) (−1SD),respectively, including for example, in the case where the largeparticle range is defined as greater than about II microns, about 47 toabout 59 percent, about 49 to about 57 percent, or about 51 to about 55percent of the total volume of the calcium carbonate powder. Inembodiments where the lower end of the large particle range is about 7.5micron, about 10 microns, about 12.5 microns, or about 15 microns,preferred volume percent ranges can be similarly calculated based on thedata in Table 7.

All ranges disclosed herein will be understood to explicitly discloseevery value within the range, each intermediate value being omittedherein for the sake of brevity. Thus, the reader will understand that,for example, the intermediate particle size range of about 0.25 to about10 microns explicitly discloses particle sizes of, for example, about0.3, 0.4, 0.5, 0.6, 0.7, 0.8 and 0.9 microns and about 1, 2, 3, 4, 5, 6,7, 8, and about 9 microns. Further, the ranges will be understood todisclose every sub-range therein. Thus, the upper and lower endpoints ofeach sub-range will include every intermediate value within the range.For example, the small particle size range of, for example, less thanabout 1 micron, will include sub-ranges of less than about 0.9, 0.8,0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or about 0.1 micron. The intermediateparticle size ranges, including for example about 0.25 to about 10microns, will explicitly disclose sub-ranges wherein the lower end isincreased in increments of 0.05 (i.e., 0.3 to 10, 0.4 to 10, etc.), 0.1(0.35 to 10, 0.45 to 10, etc.), 0.5 (0.75 to 10, 1.25 to 10, etc.), or 1micron (1.25 to 10, 2.25 to 10, etc.) and wherein the upper end of therange is decreased in increments of 0.5 (i.e., 0.25 to 9.5, 0.25 to 9,etc.) or 1 (i.e. 0.25 to 9, 0.25 to 8, 0.25 to 7, etc.), as well as anysub-ranges formed by increasing the lower endpoint and decreasing theupper end point in this manner. All such sub ranges are omitted hereinfor brevity but will be understood to be explicitly disclosed.

While the preferred embodiment described above utilize mined limestonecalcium carbonate, the invention is not so limited and also embraces insome embodiments precipitated calcium carbonate powders which meet theparticle size distribution requirements described herein. Precipitatedcalcium carbonates can be prepared having a variety of crystal habits,including cubic, prismatic, rose-shaped, needle-shaped, barrel-shapedand the like, which are expected to have different capabilities towardparacellular diffusion. Accordingly, each of the foregoing crystal formsis contemplated to be an embodiment of the invention. Typically, thoughnot always, precipitated calcium carbonate powders have a narrowerparticle size distribution than mined calcium carbonate powder whichhave been ground. Therefore, when using precipitated calcium carbonatepowders, it might be necessary to combine one or more powders to achievesufficient volume in the small, intermediate, and large particle sizeranges. It is within the skill in the art to provide powders have suchdistributions using mesh screening or similar techniques and bycombining commercially available calcium carbonate powders of varyingaverage particle size. In preferred embodiments, the calcium carbonatepowders are USP grade rather than food grade, as food grade powders maycomprise substantial levels impurities which interfere with calciumabsorption. In this regard, it will be recognized that food gradecalcium carbonate powders may be functionally very different than USP orpharmaceutical grade powders.

In determining whether a particular calcium carbonate powder meets therequirement described herein, it is preferred to measure the particlesize distributions using a Beckman Coulter LS13 320 Particle SizeAnalyzer with the Aqueous Liquid Sample Module or comparable particlesize analyzer using the parameter defined herein. The Beckman CoulterLS13 320 Particle Size Analyzer and the Aqueous Liquid Sample Module aredescribed in Beckman Coulter publication BR-9809A (2004), the contentsof which are incorporated by reference, and complies with ISO13320-1:1999 (Particle size analysis—Laser diffraction methods—Part 1:General principles) as described in Beckman Coulter publication TA-403,the content of which is incorporated by reference. The term “channeldiameter” is used synonymously with particle size.

Example 3

Due to the enhanced absorption attainable with the calcium carbonatepowders of the invention, less calcium carbonate, on a weight basis,will be required to provide a supplement which meets the DietaryReference Intakes (DRIs), as compared to other calcium carbonate powdershaving lower absorption.

The DRIs set by the Institute of Medicine of the National Academy ofSciences are provided in terms of Adequate Intakes (AIs). See StandingCommittee on the Scientific Evaluation of Dietary Reference Intakes,Food and Nutrition Board, Institute of Medicine. Dietary ReferenceIntakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride,Washington D.C.: The National Academies Press, 1997. The recommended AIfor children and teenagers 9 to 18 years olds is 1,300 mg of elementalcalcium per day. For adults of age 19 to 50 years, the AI is 1,000 mg ofelemental calcium per day and for adults over 50 the AI is 1,200 mg perday. These values reflect the recognition that not all calcium consumedis actually utilized. Rather, in the case of adults, the elementalcalcium AI values of 1,000 mg and 1,200 mg are based on the observationthat only about 30% of the calcium will be absorbed, as reported byHeaney et al., “Variability of calcium absorption,” Am. J. Clin. Nutr.47: 262-264 (1988), which is hereby incorporated by reference, and forthe 9 to 18 year olds group the value of 1,300 mg reflects a percentabsorption of 38%, as reported by Wastney et al., “Differences incalcium kinetics between adolescent girls and young women,” Am. J.Physiol. 271: R208-R216 (1996), which is hereby incorporated byreference.

Accordingly, much of the elemental calcium present in a conventionalcalcium supplement will not be absorbed through the intestine but ratherwill be excreted, as indicated by V_(f) in FIG. 1. In the case ofadults, for example, V_(f) will account for approximately 70% of theelemental calcium in a conventional calcium supplement. In contrast, thecalcium carbonate powders of the present invention exhibit asurprisingly higher percent absorption, i.e., absorption efficiency(V_(i)−V_(f))/V_(i) expressed on a percentage basis, than the relativelylow percent absorption values used to derive the recommended AI (e.g.,30%). As shown in Table 4 of Example 1, a percentage absorption of 50%or above is attainable with the inventive calcium carbonate powders,such as OMYA-Cal® USP-10-AZ (Diet 2). It will therefore be apparent thatless of the calcium carbonate powder of the present invention will berequired to provide the desired daily amount of elemental calcium ascompared to other commercially available sources of calcium.

For example, a calcium supplement having 360 mg of elemental calciumprovided by the calcium carbonate powder of the present invention (e.g.,OMYA-Cal® USP-10-AZ), which is 50% absorbable, is expected to deliverthe same amount of absorbable elemental calcium as a conventional tablethaving 600 mg of elemental calcium, which is 30% absorbable, i.e., (360mg)×(0.50)=(600 mg)×(0.30). The concomitant reduction in tablet sizewill therefore be quite large, as about 900 mg of calcium carbonatepowder according to the invention is expected to deliver the same amountof elemental calcium as about 1,500 mg of conventional calcium carbonatepowder. Put another way, by employing the calcium carbonate powers ofthe invention in place of conventional calcium carbonate powders, about40% less calcium carbonate will be required to deliver the sameabsorbable elemental calcium dose and, consequently, the tablet volumerequired to provide a given dose of absorbable elemental calcium willalso be reduced by about 40%.

It has heretofore proven impractical to formulate a single dose tabletwhich supplies the daily requirement of elemental calcium because thesize of the tablet would be larger than most consumers find tolerable toswallow. With conventional calcium carbonate powder (i.e., calciumcarbonate powder which is about 30% absorbable in adults), the AI of1,200 mg of elemental calcium would require that a single tabletcomprise about 3 g of calcium carbonate. Such a large amount of calciumcarbonate cannot be compressed into a tablet small enough to swallowwithout discomfort. Not surprisingly, commercially available calciumsupplements, such as Caltrate®, are typically provided as a two-a-dayformulation having 600 mg of elemental calcium per tablet, such that twotablets are required to provide the recommended daily AI of elementalcalcium for adults. However, with the highly bioavailable calcium formsof the present invention, a calcium supplement need only comprise 720 mgof elemental calcium, rather than 1,200 mg, to deliver the same amountof absorbable elemental calcium, i.e, (720 mg)×(0.50)=(1,200 mg)×(0.30).Because 720 mg of elemental calcium is provided by about 1,800 mg ofcalcium carbonate, once-daily tablets which are not objectionable toswallow can be prepared with the calcium carbonate powder according tothe invention, including but not limited to OMYA-Cal® USP-10-AZ.

To further evaluate the reduction in tablet size obtainable using thehighly absorbable calcium carbonate powders of the invention, as seriesof tablets were prepared as once-daily and twice-daily supplementscapable of providing amounts of absorbable calcium equivalent to the AIsof 1,000 mg, 1,200 mg, and 1,300 mg of elemental calcium per day. Ineach case, the tablets were prepared from a calcium carbonategranulation having the formulation of Table 14 which delivers about37.5% by weight elemental calcium.

TABLE 14 Component Weight % OMYA-Cal ® USP-10-AZ 93 maltodextrin 5.0mineral oil 1.0 glycerin 0.5 water 0.5

The granulation was prepared according to the method for making highdensity calcium carbonate granulation described in U.S. patentapplication Ser. No. 10/631,923, the contents of which are herebyincorporated by reference. Briefly, this method entailed mixing thecalcium carbonate powder (OMYA-Cal® USP-10-AZ) and binder (maltodextrin)in a Collette Gral Model 600 high shear mixer for about one minute atmixer speeds from about 200 to about 300 rpm, adding water heated toabout 93° C. to the mixture through a water line and mixing for anadditional period until steam stopped being produced from thecomposition, then spraying onto the composition the mineral oil andglycerin using a spray nozzle fed by a line through the head of themixer with continued mixing for about one minute. The resultinggranulation was dried to a water content of 0.5% by weight in a Carriermodel QAD/C 1260 S horizontal fluidized bed convection oven at a producttemperature between 100° C. and 150° C.

The granulation was compressed into tablets comprising 300 mg, 360 mg,390 mg, 500 mg, 600 mg, 650 mg, 720 mg, 780 mg, 1000 mg, 1200 mg, and1300 mg of elemental calcium, plus an overage of 5% by weight in eachcase, using conventional techniques. The rational for each of thesedosages is as follows: (1) For a recommended AI of 1,000 mg, once-dailyand twice-daily tablets will comprise 1,000 mg and 500 mg of elementalcalcium, respectively, based on the conventional 30% absorption value,or will comprise 600 mg and 300 mg of elemental calcium, respectively,based on the 50% absorption value of the calcium carbonate according tothe present invention; (2) For a recommended AI of 1,200 mg, once-dailyand twice-daily tablets will comprise 1,200 mg and 600 mg of elementalcalcium, respectively, based on the conventional 30% absorption value,or will comprise 720 mg and 360 mg of elemental calcium, respectively,based on the 50% absorption value of the calcium carbonate according tothe present invention; (3) For a recommended AI of 1,300 mg, once-dailyand twice-daily tablets will comprise 1,300 mg and 650 mg of elementalcalcium, respectively, based on the conventional 30% absorption value,or will comprise 780 mg and 390 mg of elemental calcium, respectively,based on the 50% absorption value of the calcium carbonate according tothe present invention. For the AI of 1,300 mg, the absorbable elementalcalcium dose is based on the fractional absorption value of 30% foradults reported by Heaney et al., rather than the value of 38% for the 9to 18 year old group reported by Wastney et al., in recognition of theemerging consensus in the art that calcium intakes for adults should beincreased.

The volume of each of the foregoing tablets was determined by one ormore techniques. The preferred method for determining tablet volumeinvolves the use of a graduated cylinder or the like to measure thevolume of glycerin, or other suitable liquid, displaced by the tablets.Preferably, a flask having an overflow spout is filled with glycerin tothe point where any increase in volume will cause glycerin to spill overinto the overflow spout and collect in a graduated cylinder. Severaltablets are then added to the flask and the volume of displaced glycerinwhich is collected in the graduated cylinder is measured and divided bythe number of tablets added to give the volume of each tablet.Alternatively, volume may be measured by laser imaging techniques or bydirect dimensional measurements using of cylindrical or disc shapedtablets, for example.

The volume of once-daily and twice-daily tablets required to deliver aneffective amount of elemental calcium equivalent to an AI of 1,000 mgare given in Table 15, for calcium carbonate powders having 50%absorption efficiency according to the invention and conventionalpowders having 30% absorption according to the prior art.

TABLE 15 Adequate Intake (AI) of 1,000 mg calcium elemental carbonatetablet tablet calcium per per tablet weight volume Comfortable tablet(mg) (mg) (g) (mL) to swallow? 50% Absorption Once-daily: 600 1,499 1.690.84 good Twice-daily: 300 749 0.86 0.44 excellent 30% AbsorptionOnce-daily: 1,000 2,498 2.79 1.35 poor Twice-daily: 500 1,249 1.41 0.67good

In one embodiment of the invention, once-daily tablets are providedcomprising an amount of highly absorbable (i.e., at least about 40%,preferably, at least about 45%, and more preferably, at least about 50%)calcium carbonate powder according to the invention sufficient tosupply, in a single tablet, an effective amount of absorbable elementalcalcium equivalent to the AI of 1,000 mg (based on an absorption valueof 30%). Preferably, the calcium carbonate powder according to theinvention are at least about 50% absorbable, in which case, once-a-daytablets according to this embodiment will typically comprise from about1,350 to about 1,650 mg, preferably from about 1,425 to about 1,575 mg,and more preferably about 1,500 mg (±5%) of the highly absorbablecalcium carbonate powders described herein, including but not limited toOMYA-Cal® USP-10-AZ. The tablets according to this embodiment, willtypically, but not necessarily, have a volume less than about 1.30 orabout 1.20 mL (cm³), preferably less than about 1.10 mL, more preferablyless than about 0.95 mL, and more preferred still, less than about 0.85mL. In a particularly interesting embodiment, about 1,500 mg (±5%) ofcalcium carbonate according to the invention will be provided in atablet having a volume in the range of about 0.75 to about 1 mL,preferably, from about 0.80 to about 0.90 mL, and will be capable ofdelivering substantially the same amount (i.e., within ±10%, preferablywithin ±5% and more preferably within ±2.5%) of absorbable calcium as:(1) 30% of the AI of 1,000 mg (i.e., 300 mg of elemental calcium);and/or (2) the amount of calcium absorbable from about 2,500 mg of aconventional calcium carbonate powder, e.g., one exhibiting about 30%absorption in adults.

In a related embodiment, twice-daily tablets are provided which,individually, comprise an amount of the highly absorbable calciumcarbonate powder according to the invention sufficient to supply aneffective amount of absorbable elemental calcium equivalent to half ofthe AI of 1,000 mg (based on an absorption value of 30%) such that twotablet are capable of providing the full AI of 1,000 mg. Preferably, thecalcium carbonate powder according to the invention are at least about50% absorbable, in which case, a tablet according to this embodimentwill typically comprise from about 700 to about 800 mg, preferably fromabout 725 to about 775 mg, and more preferably about 750 mg (±5%) of thehighly absorbable calcium carbonate powders described herein, includingbut not limited to OMYA-Cal® USP-10-AZ. The tablets according to thisembodiment, will typically, but not necessarily, have a volume less thanabout 0.60 mL, preferably less than about 0.50 mL, and more preferablyless than about 0.45 mL. In a particularly interesting embodiment, about750 mg (±5%) of calcium carbonate according to the invention will beprovided in a tablet having a volume in the range of about 0.3 to about0.6 mL, preferably, from about 0.35 to about 0.55 mL, more preferablyfrom about 0.40 to about 0.50 mL, included a representative embodimentof about 0.45 mL, and will be capable of delivering substantially thesame amount (i.e., within ±10%, preferably within ±5% and morepreferably within ±2.5%) of absorbable calcium as: (1) half of 30% ofthe AI of 1,000 mg (i.e., 150 mg of elemental calcium); and/or (2) theamount of calcium absorbable from about 1,250 mg of a conventionalcalcium carbonate powder, e.g., one exhibiting about 30% absorption inadults.

The volume of once-daily and twice-daily tablets required to deliver aneffective amount of elemental calcium corresponding to an AI of 1,200mg, for 50% absorption according to the invention and 30% absorption ofthe prior art, are given in Table 16.

TABLE 16 AI of 1,200 mg elemental calcium calcium tablet tablet (mg) percarbonate weight volume Comfortable tablet (mg) (g) (mL) to swallow? 50%Absorption Once-daily: 720 1,798 2.04 0.99 good Twice-daily: 360 8991.02 0.51 excellent 30% Absorption Once-daily: 1,200 2,997 3.37 1.66very poor Twice-daily: 600 1,449 1.69 0.84 good

In one embodiment of the invention, once-daily tablets are providedcomprising an amount of highly absorbable (i.e., at least about 40%,preferably, at least about 45%, and more preferably, at least about 50%)calcium carbonate powder according to the invention sufficient tosupply, in a single tablet, an effective amount of absorbable elementalcalcium equivalent to the AI of 1,200 mg (based on an absorption valueof 30%). In particularly interesting embodiments, the calcium carbonatepowders according to the invention are at least about 50% absorbable, inwhich case, once-a-day tablets according to this embodiment willtypically comprise from about 1,500 to about 2,500 mg, preferably fromabout 1,600 to about 2,000 mg, and more preferably about 1,800 mg (±5%)of the highly absorbable calcium carbonate powders described herein,including but not limited to OMYA-Cal® USP-10-AZ. The tablets accordingto this embodiment, will typically, but not necessarily, have a volumeless than about 1.60 or about 1.55 mL, preferably less than about 1.25mL, more preferably less than about 1.10 mL, and more preferred still,less than about 1.00 mL. In a particularly interesting embodiment, about1,800 mg (±5%) of calcium carbonate according to the invention will beprovided in a tablet having a volume in the range of about 0.75 to about1.5 mL, preferably, from about 0.80 to about 1.25 mL, more preferablyfrom about 0.9 to about 1.10 mL, and more preferred still about 1 mL,and will be capable of delivering substantially the same amount (i.e.,within ±10%, preferably within ±5% and more preferably within ±2.5%) ofabsorbable calcium as: (1) 30% of the AI of 1,200 mg (i.e., 360 mg ofelemental calcium); and/or (2) the amount of calcium absorbable fromabout 3,000 mg of a conventional calcium carbonate powder, e.g., oneexhibiting about 30% absorption in adults.

In a related embodiment, twice-daily tablets are provided which,individually, comprise an amount of the highly absorbable calciumcarbonate powder according to the invention sufficient to supply aneffective amount of absorbable elemental calcium equivalent to half ofthe AI of 1,200 mg (based on an absorption value of 30%) such that twotablet are capable of providing the full AI of 1,200 mg. Preferably, thecalcium carbonate powder according to the invention are at least about50% absorbable, in which case, a tablet according to this embodimentwill typically comprise from about 800 mg to about 1,400 mg, preferablyfrom about 850 mg to about 1,200 mg, more preferably from about 875 mgto about 1,100 mg, including a representative embodiment of about 900 mg(±5%) of the highly absorbable calcium carbonate powders describedherein, including but not limited to OMYA-Cal® USP-10-AZ. The tabletsaccording to this embodiment, will typically, but not necessarily, havea volume less than about 0.80 mL, preferably less than about 0.70 mL,and more preferably less than about 0.60 mL, and more preferred still,less than about 0.55 mL. In a particularly interesting embodiment, about900 mg (±5%) of calcium carbonate according to the invention will beprovided in a tablet having a volume in the range of about 0.4 to about0.8 mL, preferably, from about 0.45 to about 0.6 mL, more preferablyfrom about 0.45 to about 0.55 mL, included a representative embodimentof about 0.5 mL, and will be capable of delivering substantially thesame amount (i.e., within ±10%, preferably within ±5% and morepreferably within ±2.5%) of absorbable calcium as: (1) half of 30% ofthe AI of 1,200 mg (i.e., 180 mg of elemental calcium); and/or (2) theamount of calcium absorbable from about 1,450 mg of a conventionalcalcium carbonate powder, e.g., one exhibiting about 30% absorption inadults.

The volume of once-daily and twice-daily tablets required to deliver aneffective amount of elemental calcium corresponding to an AI of 1,300mg, for 50% absorption according to the invention and 30% absorption ofthe prior art, are given in Table 17.

TABLE 17 AI of 1,300 mg elemental calcium calcium carbonate tablettablet (mg) per per tablet weight volume Comfortable tablet (mg) (g)(mL) to swallow? 50% Absorption Once-daily: 780 1,948 2.21 1.07 goodTwice-daily: 390 974 1.12 0.57 excellent 30% Absorption Once-daily:1,300 3,247 3.65 1.84 very poor Twice-daily: 650 1,623 1.83 0.88 good

In one embodiment of the invention, once-daily tablets are providedcomprising an amount of highly absorbable (i.e., at least about 40%,preferably, at least about 45%, and more preferably, at least about 50%)calcium carbonate powder according to the invention sufficient tosupply, in a single tablet, an effective amount of absorbable elementalcalcium equivalent to the AI of 1,300 mg (based on an absorption valueof 30%). In particularly interesting embodiments, the calcium carbonatepowders according to the invention are at least about 50% absorbable, inwhich case, once-a-day tablets according to this embodiment willtypically comprise from about 1,750 to about 3,000 mg, preferably fromabout 1,800 to about 2,500 mg, more preferably from about 1,900 mg toabout 2,000 mg, and more preferred still, about 1,950 mg (±5%) of thehighly absorbable calcium carbonate powders described herein, includingbut not limited to OMYA-Cal® USP-10-AZ. The tablets according to thisembodiment, will typically, but not necessarily, have a volume less thanabout 1.60 or about 1.55 mL, preferably less than about 1.75 mL, morepreferably less than about 1.50 mL, and more preferred still, less thanabout 1.15 mL. In a particularly interesting embodiment, about 1,950 mg(±5%) of calcium carbonate according to the invention will be providedin a tablet having a volume in the range of about 0.80 to about 1.75 mL,preferably, from about 0.90 to about 1.50 mL, more preferably from about0.95 to about 1.25 mL, and more preferred still from about 1 mL to about1.15 mL, including a representative embodiment of about 1.10 mL, andwill be capable of delivering substantially the same amount (i.e.,within ±10%, preferably within ±5% and more preferably within ±2.5%) ofabsorbable calcium as: (1) 30% of the AI of 1,300 mg (i.e., 390 mg ofelemental calcium); and/or (2) the amount of calcium absorbable fromabout 3,250 mg of a conventional calcium carbonate powder, e.g., oneexhibiting about 30% absorption in adults.

In a related embodiment, twice-daily tablets are provided which,individually, comprise an amount of the highly absorbable calciumcarbonate powder according to the invention sufficient to supply aneffective amount of absorbable elemental calcium equivalent to half ofthe AI of 1,300 mg (based on an absorption value of 30%) such that twotablet are capable of providing the full AI of 1,300 mg. Preferably, thecalcium carbonate powders according to the invention are at least about50% absorbable, in which case, a tablet according to this embodimentwill typically comprise from about 900 mg to about 1,500 mg, preferablyfrom about 925 mg to about 1,200 mg, more preferably from about 950 mgto about 1,100 mg, including a representative embodiment of about 975 mg(±5%) of the highly absorbable calcium carbonate powders describedherein, including but not limited to OMYA-Cal® USP-10-AZ. The tabletsaccording to this embodiment, will typically, but not necessarily, havea volume less than about 0.85 mL, preferably less than about 0.8 mL,more preferably less than about 0.70 mL, and more preferred still, lessthan about 0.6 mL. In a particularly interesting embodiment, about 975mg (±5%) of calcium carbonate according to the invention will beprovided in a tablet having a volume in the range of about 0.45 to about0.8 mL, preferably, from about 0.5 to about 0.7 mL, more preferably fromabout 0.55 to about 0.65 mL, included a representative embodiment in thereange of about 0.55 mL to about 0.60 mL, and will be capable ofdelivering substantially the same amount (i.e., within ±10%, preferablywithin ±5% and more preferably within*2.5%) of absorbable calcium as:(1) half of 30% of the AI of 1,300 mg (i.e., 195 mg of elementalcalcium); and/or (2) the amount of calcium absorbable from about 1,625mg of a conventional calcium carbonate powder, e.g., one exhibitingabout 30% absorption in adults.

The actual tablets for which the volume and weights were measured inTables 15-17 included a 5% overage in the amount of calcium carbonate toaccount for manufacturing variability and to ensure that every tabletdelivers at least the amount of elemental calcium specified.

In addition to the foregoing, it is contemplated that a tabletcomprising 325 mg of elemental calcium provided by about 812 mg ofOMYA-Cal® USP-10-AZ or other calcium carbonate powder according to theinvention will be especially useful, particularly for administration tochildren supplement for children. In one embodiment, the tablet willcomprise from about 812 mg to about 853 mg of OMYA-Cal® USP-10-AZ orother suitable powder according to the invention. It is believed thatsuch a supplement will have a volume between about 0.45 and about 1 mL,preferably between about 0.6 and about 0.9 mL, including representativeembodiments of about 0.7 mL, 0.75 mL, 0.8 mL, and 0.85 mL.

While this example used the calcium carbonate powder OMYA-Cal®USP-10-AZ, any of the calcium powders described herein, including thosedescribed in Example 2, are contemplated to be equally suitable inpreparing the once-daily and twice daily tablets described herein. Thetablets according to this example are contemplated to be especiallysuited for use in the methods described herein, including the methodsfor treating or preventing osteoporosis and building bone mass.

It will be understood that the foregoing embodiments directed toproviding the elemental calcium equivalent of the AIs of 1,000 mg, 1,200mg, and 1,300 mg elemental calcium are merely illustrative of thevarious tablets that can be prepared according to the invention. Forexample, it will be observed that for any desired amount of elementalcalcium delivery, tablets of the present invention will be smaller thanprior art tablets due to the fact that less of the highly absorbablecalcium carbonate of the invention need be included to achieve the sameeffective delivery of absorbable calcium as compared to prior artcalcium carbonate powders. Further, while this example describes tabletswhich are prepared using the methods for making very small tabletsdescribed in U.S. patent application Ser. No. 10/631,923, it will beunderstood that a comparable reduction in size (e.g., about 40%) can beachieved using any granulation and tableting method known in the art,due to the fact that less calcium carbonate powder is required todeliver a comparable amount of absorbable elemental calcium than priorart powders.

The most preferred calcium carbonate powders according the presentinvention will have a percent absorption, in children and/or adults, ofat least about 50%. However, the invention is not so limited andembraces all calcium carbonate powders having particle sizedistributions defined herein, wherein the percent absorption in adultsis at least about 35%, preferably at least about 40%, and morepreferably at least about 45% and/or the percent absorption in childrenand teens aged 9 to 18 is at least about 35%, preferably at least about40%, and more preferably at least about 45%. It will be understood thatthese values represent the average percent absorption in a populationand there may be significant variability on an individual basis.

All patent and non-patent literature referenced in this specification ishereby incorporated by reference.

The invention having been described by the foregoing description of thepreferred embodiments, it will be understood that the skilled artisanmay make modifications and variations of these embodiments withoutdeparting from the spirit or scope of the invention as set forth in thefollowing claims:

We claim:
 1. A confectionery comprising (1) a USP grade calciumcarbonate powder having a particle size distribution characterized by aD₅₀ value, on a volume basis between about 9.8 μm and about 13.5 μm, aD₉₀ value, on a volume basis, between about 26.1 μm and about 31.7 μm,and at least 30% of the total volume of particles having sizes betweenabout 1 μm and about 11 μm, a mode between 18.00 and 23.81 μm, a meanbetween 12.99 and 14.31 μm, a D[3,2] value between 2.39 and 2.53 μm, amean/median ratio of 1.15 to 1.62, a coefficient of variation (%)between 77.2 and 79.3, and a specific surface area from 8753 to 9268cm²/g; and (2) at least about 400 I.U. of vitamin D.
 2. A pharmaceuticalcomposition comprising: (1) a USP grade calcium carbonate powder havinga particle size distribution characterized by a D₅₀ value, on a volumebasis, between about 9.8 μm and about 13.5 μm, a D₉₀ value, on a volumebasis, between about 26.1 μm and about 31.7 μm, and at least 30% of thetotal volume of particles having sizes between about 1 μm and about 11μm, a mode between 18.00 and 23.81 μm, a mean between 12.99 and 14.31nm, a D[3,2] value between 2.39 and 2.53 nm, a mean/median ratio of 1.15to 1.62, a coefficient of variation (%) between 77.2 and 79.3, and aspecific surface area from 8753 to 9268 cm²/g; and (2) at least about400 I.U. of vitamin D.
 3. A multi-vitamin comprising: (1) a USP gradecalcium carbonate powder having a particle size distributioncharacterized by a D₅₀ value, on a volume basis, between about 9.8 μmand about 13.5 μm, a D₉₀ value, on a volume basis, between about 26.1 μmand about 31.7 μm, and at least 30% of the total volume of particleshaving sizes between about 1 μm and about 11 μm, a mode between 18.00and 23.81 μm, a mean between 12.99 and 14.31 μm, a D[3,2] value between2.39 and 2.53 μm, a mean/median ratio of 1.15 to 1.62, a coefficient ofvariation (%) between 77.2 and 79.3, and a specific surface area from8753 to 9268 cm²/g; and (2) one or more vitamins selected from the groupconsisting of: between 1 and about 35,000 IU of vitamin A; between 1 andabout 1,000 mg of vitamin C; between 1 and about 4,000 IU of vitamin D;between 1 and about 450 IU of vitamin E; between 1 and about 250 mcg ofvitamin K; between 1 and about 15 mg of vitamin B-1 (thiamin); between 1and about 17 mg of vitamin B-2 (riboflavin); between 1 and about 200 mgof vitamin B-3 (niacin); between 1 and about 100 mg of vitamin B-5(pantothenic acid); between 1 and about 30 mg of vitamin B-6(pyridoxine); between 1 and about 4,000 mcg of vitamin B-9 (folic acid);between 1 and about 250 mcg of vitamin B-12 (cobalamin); and between 1and about 1,000 mcg of vitamin H (biotin); and combinations thereof; and(3) one or more minerals selected from the group consisting of: between1 and about 180 mg of iron; between 1 and about 1,100 mg of phosphorous;between 1 and about 1,500 mcg of iodine; between 1 and about 4,000 mg ofmagnesium; between 1 and about 150 mg of zinc; between 1 and about 600mcg of selenium; between 1 and about 20 mg of copper; between 1 andabout 20 mg of manganese; between 1 and about 2,000 mcg of chromium; andbetween 1 and about 750 mcg of molybdenum; between 0.001 and about 0.1mg of tin; between 1 and about 100 mcg of vanadium; between 0.5 and 50mcg of nickel; and combinations thereof.